U.S. patent number 10,279,974 [Application Number 14/657,535] was granted by the patent office on 2019-05-07 for support and packaging for membranes.
The grantee listed for this patent is OSIRIS THERAPEUTICS, INC.. Invention is credited to Alla Danilkovitch, Yi Duan-Arnold, Alexandra Gyurdieva, Jin-Qiang Kuang, Steven Michael Sinclair.
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United States Patent |
10,279,974 |
Duan-Arnold , et
al. |
May 7, 2019 |
Support and packaging for membranes
Abstract
A support assembly for supporting a biological product (e.g.,
membrane) in an operative position. The support assembly has a base
and a cover. A membrane receiving portion of the base defines a
plurality of perforations that extend between top and bottom
surfaces of the product receiving portion. The cover is releasably
coupled to the base in a product-covering position in which the
cover overlies the product receiving portion of the base. In the
operative position, the biological product engages the top surface
of the product receiving portion and the bottom surface of the
cover.
Inventors: |
Duan-Arnold; Yi (Ellicott City,
MD), Danilkovitch; Alla (Columbia, MD), Gyurdieva;
Alexandra (Elkridge, MD), Kuang; Jin-Qiang (Woodstock,
MD), Sinclair; Steven Michael (Ellicott City, MD) |
Applicant: |
Name |
City |
State |
Country |
Type |
OSIRIS THERAPEUTICS, INC. |
Columbia |
MD |
US |
|
|
Family
ID: |
54068141 |
Appl.
No.: |
14/657,535 |
Filed: |
March 13, 2015 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20150259119 A1 |
Sep 17, 2015 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61953716 |
Mar 14, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B65B
5/04 (20130101); A61F 15/001 (20130101); B65D
65/02 (20130101); A61F 2/0095 (20130101); B65D
85/70 (20130101); B65D 77/26 (20130101); B65B
55/22 (20130101); A61B 2090/0815 (20160201); A61F
2/105 (20130101); A61B 2090/0816 (20160201) |
Current International
Class: |
B65D
77/26 (20060101); A61F 2/00 (20060101); B65B
55/22 (20060101); B65B 5/04 (20060101); B65D
85/00 (20060101); B65D 65/02 (20060101); A61F
15/00 (20060101); A61F 2/10 (20060101); A61B
90/00 (20160101) |
Field of
Search: |
;206/570 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
European Search Report dated Oct. 12, 2017 by the European Patent
Office for EP Patent Application No. 15762235.8, which was filed on
Mar. 13, 2015 and published as EP 3116459 on Jan. 18, 2017
(Applicant--Osiris Therapeutics, Inc.) (7 pages). cited by
applicant .
International Search Report and Written Opinion of the
International Searching Authority dated Jun. 11, 2015 for
International Application No. PCT/US2015/020502, filed on Mar. 13,
2015 (Applicant--Osiris Therapeutics, Inc. //
Inventor--Duan-Arnold, et al.) (34 pages). cited by applicant .
Office Action dated Sep. 7, 2018 by the European Patent Office for
Patent Application No. 15762235.8, which was filed on Mar. 13, 2015
and published as EP 3116459 on Jan. 18, 2017 (Inventor--Duan-Arnold
et al.; Applicant--Osiris Therapeutics, Inc.) (3 pages). cited by
applicant.
|
Primary Examiner: Reynolds; Steven A.
Assistant Examiner: Pagan; Javier A
Attorney, Agent or Firm: Ballard Spahr LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of the filing
date of U.S. Provisional Patent Application No. 61/953,716, filed
Mar. 14, 2014, entitled "Support and Packaging for Membranes,"
which is incorporated by reference herein in its entirety.
Claims
What is claimed is:
1. A membrane product package comprising: a support assembly
comprising: a base having a longitudinal axis and comprising a
product receiving portion, the product receiving portion having a
top surface and an opposed bottom surface that are spaced apart
relative to a vertical axis that is perpendicular to the
longitudinal axis of the base, wherein the product receiving
portion comprises a plurality of perforations extending between the
top and bottom surfaces of the product receiving portion; and a
cover having a longitudinal axis, a top surface, and an opposed
bottom surface, wherein the cover is configured for releasable
coupling to the base in a product-covering position, and wherein,
in the product-covering position, the cover overlies the product
receiving portion of the base; and a membrane positioned in an
operative position between the product receiving portion of the
base and the cover, wherein the membrane is a placental tissue
product, wherein the membrane is positioned in engagement with at
least a portion of the top surface of the product receiving portion
of the base and at least a portion of the bottom surface of the
cover, wherein the membrane is attached to the top surface of the
product receiving portion of the base at at least one attachment
point, and wherein the base and the cover cooperate to support the
membrane in the operative position.
2. The membrane product package of claim 1, wherein the base
further comprises a handling portion positioned adjacent to the
product receiving portion relative to the longitudinal axis of the
base.
3. The membrane product package of claim 2, wherein, in the
product-covering position, the cover does not overlap with the
handling portion of the base.
4. The membrane product package of claim 1, wherein in the
product-covering position, the longitudinal axis of the cover is
positioned in substantial alignment with the longitudinal axis of
the base.
5. The membrane product package of claim 4, wherein the product
receiving portion of the base has a longitudinal length and a
width, wherein the cover has a longitudinal length and a width, and
wherein the longitudinal length of the cover is substantially equal
to the longitudinal length of the product receiving portion.
6. The membrane product package of claim 5, wherein the width of
the cover is substantially equal to the width of the product
receiving portion.
7. The membrane product package of claim 1, wherein the cover has a
plurality of corners, and wherein at least one of the corners of
the cover is rounded.
8. The membrane product package of claim 7, wherein the cover has
four rounded corners.
9. The membrane product package of claim 8, wherein the product
receiving portion of the base has two rounded corners, and wherein,
in the product-covering position, two rounded corners of the cover
overlie the two rounded corners of the product receiving portion of
the base.
10. The membrane product package of claim 1, wherein the plurality
of perforations of the product receiving portion of the base are
substantially evenly distributed throughout the product receiving
portion.
11. The membrane product package of claim 1, wherein the plurality
of perforations of the product receiving portion of the base are
randomly distributed throughout the product receiving portion.
12. The membrane product package of claim 1, wherein each
perforation of the plurality of perforations has a respective
diameter ranging from about 0.1 mm to about 5 mm.
13. The membrane product package of claim 1, wherein each
perforation of the plurality of perforations has a respective
center point, and wherein the center points of neighboring
perforations are spaced apart by a distance ranging from about 0.35
mm to about 10 mm.
14. The membrane product package of claim 1, wherein the membrane
is attached to the top surface of the product receiving portion of
the base at at least three attachment points.
15. The membrane product package of claim 1, wherein the top
surface of the product receiving portion of the base is attached to
the cover at at least one attachment point.
16. The membrane product package of claim 1, wherein the cover is
attached to the membrane at at least one attachment point.
17. The membrane product package of claim 16, wherein the cover is
attached to the membrane at at least two attachment points.
18. The membrane product package of claim 16, wherein the top
surface of the product receiving portion of the base is attached to
the cover at at least one attachment point.
19. The membrane product package of claim 1, wherein the top
surface of the product receiving portion of the base is attached to
the cover at at least one attachment point.
20. The membrane product package of claim 1, wherein the membrane
is a chorionic membrane product.
21. The membrane product package of claim 1, wherein the membrane
is an amniotic membrane product.
22. The membrane product package of claim 1, wherein the membrane
and the top surface of the product receiving portion of the base
have sufficient surface traction to maintain the membrane in the
operative position following removal of the cover from the
base.
23. The membrane product package of claim 1, wherein the membrane
and the top surface of the product receiving portion of the base
have a first surface traction, wherein the membrane and the cover
have a second surface traction, and wherein the second surface
traction is lower than the first surface traction.
24. A method of producing the membrane product package of claim 1,
comprising: positioning the membrane in the operative position
between the product receiving portion of the base and the cover,
wherein the membrane is positioned in engagement with at least a
portion of the top surface of the product receiving portion of the
base and at least a portion of the bottom surface of the cover,
wherein the step of positioning the membrane in the operative
position comprises: attaching the membrane to the top surface of
the product receiving portion at at least one attachment point; and
releasably coupling the cover to the base in the product-covering
position.
25. The method of claim 24, wherein the step of positioning the
membrane in the operative position further comprises: attaching the
membrane to the cover at at least one attachment point.
26. The method of claim 25, wherein the method further comprises
positioning the base, the membrane, and the cover within a
cryopreservation solution, wherein the plurality of perforations of
the product receiving portion provide contact between the membrane
and the cryopreservation solution sufficient to cryopreserve the
membrane.
27. A kit for repairing a tissue defect, comprising: a container;
and a membrane product package positioned within the container, the
membrane product package comprising: a support assembly having: a
base having a longitudinal axis and comprising a product receiving
portion, the product receiving portion having a top surface and an
opposed bottom surface that are spaced apart relative to a vertical
axis that is perpendicular to the longitudinal axis of the base,
wherein the product receiving portion comprises a plurality of
perforations extending between the top and bottom surfaces of the
product receiving portion; and a cover having a longitudinal axis,
a top surface, and an opposed bottom surface, wherein the cover is
configured for releasable coupling to the base in a
product-covering position, and wherein, in the product-covering
position, the cover overlies the product receiving portion of the
base; and a membrane positioned in an operative position between
the product receiving portion of the base and the cover, wherein
the membrane is a placental tissue product, wherein the membrane is
positioned in engagement with at least a portion of the top surface
of the product receiving portion of the base and at least a portion
of the bottom surface of the cover, wherein the membrane is
attached to the top surface of the product receiving portion of the
base at at least one attachment point, and wherein the base and the
cover cooperate to support the membrane in the operative
position.
28. The kit of claim 24, further comprising a cryopreservation
solution.
Description
BACKGROUND
Products are increasingly being used for treatment of wounds,
burns, lacerations or surgical excisions. However, to use such
products, there needs to be a method of manufacturing, packaging
and applying the product that maintains the integrity of the
product (including membranes) during these processes. Conventional
packaging for applying a biological or membrane product does not
lend itself to convenient application, and had multiple failings
including its inability to provide real time sizing and
directionality, among others. Conventional bandages and dressings,
for example, fail to adequately protect large-scale, deep, oddly
shaped and other types of wounds or tissue defects. Therefore,
various alternatives have been explored in the art. Among these
alternatives are split- and full-thickness grafts of cadaver or
porcine skin, human allografts, cultured skin equivalents and
autografts. Most of these membranes, including tissue or tissue
equivalent products/synthetic products contain, in at least some
aspects, a morphology similar to actual human skin, which has an
epithelial layer on the top and connective tissue with fibroblasts
or other types of cells on the bottom facing the wound and/or
damaged tissue. Such products can be considered to have
directionality. Further, when such membranes are used to treat a
variety of wounds (or tissue defects), the preferred orientation of
the wound, tissue, graft or applied biological product is such that
the connective tissue layer rests on the wound bed while the
epithelial layer is away from the wound bed.
Challenges exist with conventional packaging systems for the
storage, transport and the delivery or application of membranes to
various human or animal structures needing treatment such as wounds
or tissue defects. For example, the tensile strength of the grafts,
tissues, or membranes is such that they often cannot support their
own weight and tear if suspended by an edge. For this reason, these
types of graft, tissue or membrane products are often mounted on a
carrier paper and then packaged into a sealable container (such as
a bag), which contains a substantial amount of liquid (e.g., a
biomedium such as a biosolution or bioprotectant). Typically, the
attachment of the graft to the carrier paper, however, is
relatively weak. Thus, during manufacture, transportation to its
end use site, and finally during handling prior to application to a
wound (or tissue defect), the tissue or membrane may separate from
the carrier paper voluntarily or inadvertently, due to shear forces
of liquid moving around in the overall packaging. As a result, the
tissue, graft or membrane to be applied may curl, attach to itself,
attach to other aspects of the packaging, tear, or in some other
fashion become unusable for final application to the human or
animal. This results in significant waste, time loss, patient
and/or care provider dissatisfaction and cost, and ineffective
therapeutic treatment of the wound or tissue defect, among other
negative attributes. In addition, if a graft or membrane product
being supplied is cryopreserved, complete thawing of all ice
crystals (e.g., of the biomedium or cryoprotectant contained in the
container along with the tissue, graft, or membrane to be finally
applied) is necessary prior to the product's final application to a
human or animal. This thawing procedure can last for several
minutes (e.g., up to 30 minutes or more) depending upon the volume
of liquid and other material to be thawed within the packaging.
This thawing wait time and additional procedure make such
conventional tissue, graft or membrane products and product
packaging inconvenient for health care providers who may be
treating several wounds during any given period of time.
Finally, concerns also exist with current conventional application
and delivery of tissue, graft or membrane-based
products/systems/packages. If the membrane, tissue or graft needs
to be separated from the packaging (e.g., a carrier paper or
carrier bottom paper) and at the same time kept in a proper
orientation (e.g., epithelial on top and connective tissue on the
bottom) for delivery to the patient site such as a wound (or tissue
defect), then the packaging must so indicate in a clear manner and
be capable of maintaining that orientation during manufacture,
transit and final application This becomes even more difficult to
achieve when the size of the supplied graft, tissue or membrane is
small. Once the graft, tissue or membrane folds over upon itself
(or becomes disorientated in some other fashion), it is very
difficult to restore the biological material to its original planar
configuration, for example, and essentially impossible to make the
appropriate final application to the wound.
Therefore, there is a need within the art for a new package,
packaging system, composition, device, article of manufacture and
method of delivery utilizing such materials that overcomes these
deficiencies within the conventional art.
SUMMARY
Described herein, in one aspect, is a support assembly for
supporting a biological product (e.g., a membrane) in an operative
position. The support assembly can have a base and a cover. The
base can have a longitudinal axis and comprise a product receiving
portion. The product receiving portion can have a top surface and
an opposed bottom surface that are spaced apart relative to a
vertical axis that is perpendicular to the longitudinal axis of the
base. The product receiving portion can have at least one
traction-creating feature, which can be selected from the group
consisting of (i) a rough top surface; and (ii) a plurality of
perforations that extend between the top and bottom surfaces of the
product receiving portion. The cover can have a longitudinal axis,
a top surface, and an opposed bottom surface. The cover can be
configured for releasable coupling (optionally, attachment) to the
base in a product-covering position. In the product-covering
position, the cover overlies the product receiving portion of the
base. The base and the cover can be configured to cooperate to
support the biological product in the operative position. In the
operative position, the biological product is positioned in
engagement with at least a portion of the top surface of the
product receiving portion of the base and at least a portion of the
bottom surface of the cover.
In another aspect, described herein is a membrane product package
comprising a membrane and a support assembly as disclosed herein.
The membrane product package includes a membrane that is positioned
in an operative position between the product receiving portion of
the base and the cover. The membrane can be positioned in
engagement with at least a portion of the top surface of the
product receiving portion of the base and at least a portion of the
bottom surface of the cover.
Also described is a method of producing a membrane product package
as disclosed herein. The method can comprise positioning a membrane
in an operative position between the product receiving portion of
the base and the cover of a support assembly as disclosed herein.
The membrane can be positioned in engagement with at least a
portion of the top surface of the product receiving portion of the
base and at least a portion of the bottom surface of the cover.
Additionally, described herein is a method of applying a membrane
using a membrane product package as disclosed herein. The method
can comprise removing the cover from the membrane product package
to expose a top surface of the membrane. Following removal of the
cover, the membrane can remain in the operative position, which
generally corresponds to the orientation in which the membrane is
to be applied. The method can further comprise sliding the membrane
relative to the top surface of the product receiving portion of the
base to disengage the membrane from the top surface of the product
receiving portion of the base and permit selective application of
the membrane as further disclosed herein.
Further described is a kit for repairing a tissue defect. The kit
can comprise a. membrane product package as disclosed herein and
instructions for applying the membrane to repair the tissue
defect.
More generally, in some aspects and embodiments, the present
technology provides a device (e.g., a support assembly),
composition (e.g., a membrane product package), article of
manufacture or system comprising: a base comprising at least one
product (e.g., membrane) receiving portion; a cover; and at least
one location in which the base and the cover are in communication
(e.g., coupled to one another through a membrane or attached to one
another as further disclosed herein). In some embodiments, the
device, composition, article of manufacture or system further
comprises a membrane, tissue, graft or other biological material(s)
temporarily connected, attached, adhered, or operatively associated
with the cover, the base or both. The base and the cover can be
positioned in communication via at least one temporary or removable
attachment between the base and the membrane, the membrane and the
cover, and/or the base and the cover.
In some aspects or embodiments, the product (e.g., membrane)
receiving portion of the present technology comprises a structured
surface that is configured to promote adhesion of a membrane or
other biological product to the product receiving portion as
further disclosed herein. Such structured surfaces are referred to
herein as "traction-creating features." In other aspects or
embodiments of the present technology, the traction-creating
features can include one or more of a rough surface; a plurality of
perforations; a surface comprising a plurality of channels; a
surface comprising a plurality of grooves; a surface comprising a
plurality of indentations; or a surface comprising a plurality of
porations. In exemplary aspects, the rough surface can be one or
more of an abraded surface, a scratched surface, an uneven surface,
a gritty-type surface (yet, preferably free or substantially free
of loose particulate), or a bumpy surface, among others. In some
aspects, the traction-creating feature comprises at least one
perforation, at least one channel, at least one groove or at least
one indentation, wherein, in some instances, the at least one
perforation, at least one channel, at least one groove and/or at
least one indentation has a complex pattern. In some aspects or
embodiments, the base further comprises a handling portion, which
can optionally be adjacent to the membrane receiving portion. In
further aspects or embodiments, the handling portion does not
overlap with the cover. In still further aspects or embodiments,
the handling portion comprises at least one tab. In some aspects or
embodiments, the tab spans the entire width of the base. In other
aspects or embodiments, the cover spans the entire product (e.g.,
membrane) receiving portion of the base. However, segments,
portions or parts of the width of the base or membrane receiving
portion are also envisaged.
In additional aspects or embodiments, the at least one location in
which the base and cover are in communication (preferably
temporarily) with each other comprises, for example, at least one
cauterization point, at least one point made by an ultrasonic
welder, or at least one point comprising a biocompatible adhesive.
In other aspects or embodiments, the at least one location in which
the base and cover are in communication (preferably temporary
communication) with one another comprises a plurality of points. In
still further aspects and embodiments of the present technology,
the base and the cover are formed from a single piece of
biocompatible plastic or other suitable biopolymer suitable for use
with membranes, tissues, grafts, or other biological materials. In
additional aspects or embodiments of the present technology, the
base and the cover are separate pieces of biocompatible plastic or
biopolymer or other biocompatible material. In other aspects or
embodiments, the base and the cover are made of the same type of
biocompatible plastic or other biopolymer, biocopolymer or other
biocompatible material.
Some aspects of the present technology provide a composition
comprising: a base comprising at least one membrane receiving
portion; at least one membrane; at least one cover; and at least
one location in which the base and the cover are in communication,
wherein the membrane is positioned between the base and the cover.
In other aspects or embodiments, the base further comprises at
least one handling portion. In still further aspects or
embodiments, the handling portion can be adjacent to the membrane
receiving portion.
Moreover, additional aspects or embodiments of the present
technology provide a cryopreserved membrane composition comprising:
a) any of the compositions, devices, articles of manufacture,
devices or systems of the present technology disclosed herein; and
b) at least one cryopreservation medium or other compatible
biological medium.
In other instances of the present technology a kit is provided
comprising: any of the devices, articles of manufacture,
compositions, or systems of the present technology described
herein; and instructions or guides for sizing, orienting, and/or
applying, connecting or adhering at least one membrane between the
base and the cover of the device, wherein the base and the cover
have at least one location which is adapted to be in communication
with each other. Alternatively, these aspects and embodiments of
the present technology can also include at least one, preferably
more than one, point of connection between the cover and the
membrane, the base and the membrane, and/or the cover and the base.
Additionally, the kit aspects and embodiments of the present
technology can further comprise an adhesive. The adhesive may be an
adhesive that is biologically compatible, or other suitable
biocompatible materials to connect the cover and the base, to
connect the base to the membrane, or to connect the
membrane-covered base to the cover. The adhesive may be
biocompatible, able to withstand physical or chemical alterations
by solutions and solvents (e.g., a cryopreservation solution),
and/or to withstand a wide range of temperatures (for example, from
about 60.degree. C..+-.5.degree. C. to about -196.degree.
C..+-.5.degree. C., as described herein.
In some aspects or embodiments of the present technology pertaining
to a kit, instructions can further comprise at least one method of
temporarily adhering, connecting, or applying the base to a first
side of the membrane, wherein the method comprises applying at
least one biocompatible adhesive to at least one location between
the base and a first side of the membrane to form a temporary bond
between the membrane and the base. In some instances, the
instructions further comprise methods of applying the at least one
adhesive to at least one location on a first side of a cover and
the second side of the membrane to temporarily bond the cover to
the second side of the membrane, forming a cover-membrane-base
configuration.
In other aspects, the instructions included with the kits of the
present technology provide a method of temporarily and sufficiently
coupling (e.g., connecting, attaching, applying, adhering, or
indirectly securing through the membrane) the cover to the base
wherein the membrane is located between the cover and base (e.g.,
similar to a sandwich-like configuration), wherein the method
further comprises applying at least one adhesive (or other
biocompatible material) to at least one point between the cover and
the membrane-covered base and/or between the cover and the
membrane.
It should be appreciated by those skilled in the art that other
attachment mechanisms and methods can be utilized to attach the
cover to the base as well as the cover to the membrane and to
attach the base to the membrane as well as the cover and base to
the membrane. For example, in some aspects and embodiments of the
present technology, the kit includes instructions for cauterizing
at least one point of the cover to the base, wherein the membrane
is located between the cover and base. In some instances, the
instructions provide a method of cauterizing the membrane to the
base at least at one point, alternatively at least at two points,
alternatively at least at three points, alternatively at least at
four points, alternatively at least at five points, alternatively
at least at six points. In other instances, the instructions
further provide instructions on cauterizing the cover to the
membrane-base at least at one point, alternatively at two points,
alternatively at least at three points. The instructions provide a
method of cauterizing the cover, membrane and base such that the
membrane is disposed between the cover and base. In alternative
aspects or embodiments of the present technology, the instructions
can further comprise at least one method of maintaining the
directionality of the membrane, the method comprising the step of
adhering a first side of the membrane to the base in a specific
orientation and/or direction desired (e.g., in the operative
position).
In still further aspects or embodiments of the present invention,
the kit can also further comprise at least one set of instructions
for cryopreserving the device, composition, article of manufacture
or system of the present technology comprising at least one
membrane to be cryopreserved. With respect to these particular
aspects and embodiments, the cryopreservation step comprises, for
example, cryofreezing the device, composition, article of
manufacture, or system of the present technology containing the
membrane at about -18 to -20.degree. C..+-.5.degree. C. to about
-196.degree. C..+-.5.degree. C., in some aspects from about
-80.degree. C. to about -196.degree. C..+-.5.degree. C. For
acellular membranes, freezing may take place from about
-18--20.degree. C..+-.5.degree. C. to about -196.degree.
C..+-.5.degree. C. For membranes containing viable cells, freezing
may take place from about -45.degree. C..+-.5.degree. C. to about
-196.degree. C..+-.5.degree. C. In aspects or embodiments of the
present technology, the kit can further comprise instructions for
thawing the cryopreserved membrane while a component of the device,
composition, article of manufacture, or system described
herein.
In some aspects, the kit further comprises instructions for
applying the membrane to a human or animal in need thereof.
In some instances, the present technology provides a kit for
repairing a tissue defect comprising: a cryopreserved composition,
device, article of manufacture, or system described herein; and
instructions for applying the cryopreserved membrane or biological
material to the tissue defect. In some aspects, the kit further
comprises instructions for thawing the cryopreserved composition.
In some aspects, the kit comprises further instructions on
maintaining the directionality of the membrane while being applied
to the tissue defect. In some aspects, the kit further comprises
instructions for removal of the cover. In some aspects, the kit
further comprises instructions for maintaining the directionality
of the membrane. In some aspects, the kit further comprises
instructions for removing the membrane from the base.
In further instances, the present technology provides a method of
maintaining the directionality of a membrane during storage,
cryopreservation, or during application to a subject comprising:
preparing a membrane, wherein the membrane is orientated having a
first and a second side (e.g., a top surface and a bottom surface),
wherein the first and second side comprise different compositions,
structures or properties; b) adhering the membrane to the device,
system or article of manufacture described herein comprising a base
and a cover, wherein the membrane is disposed between the base and
the cover; and wherein the first side of the membrane is facing the
base and the second side of the membrane is facing the cover; and
wherein device further comprises a label to indicate
orientation.
In still other aspects, described herein is a method of applying a
membrane to a human or animal in need thereof, comprising:
obtaining a composition, system or article of manufacture as
described herein which has been cryopreserved and frozen; thawing
the composition, system or article of manufacture; optionally
rinsing the membrane in a sterile physiological solution; removing
the cover from the membrane and base; and applying the membrane
from the base onto the human or animal to retain directionality of
the membrane.
In yet further instances, the present technology provides a method
of maintaining integrity of a membrane during cryopreservation,
comprising: providing a device as described herein; adhering a
membrane to at least an area of the membrane receiving portion of
the base; adhering the cover to the base (optionally, through the
membrane, which can be directly adhered to the base), wherein the
membrane is between the cover and the base; and placing the device
comprising the membrane into a container; and contacting the
container with sterile cryopreservation solution, wherein the
device comprising the membrane is submerged in the cryopreservation
solution; and cryopreserving the container at a temperature of
about -80.degree. C. to about -196.degree. C., wherein the
integrity of the membrane is maintained once the membrane is thawed
to room temperature.
In some aspects, described is a method of treating a wound
comprising applying a membrane of any one of the compositions,
systems or articles of manufacture described herein to a human or
animal in need thereof.
Some aspects provide a system comprising: a base comprising a
membrane receiving portion; and a cover; and at least one location
in which the base and the cover are in communication. In some
aspects, the system further comprises a membrane, wherein the
membrane is disposed between the cover and the base. In these
aspects, the base and the cover can be in communication at at least
one attachment point (at least one temporary or removable
attachment between the base and the cover, the base and the
membrane, and/or the cover and the membrane).
In some aspects, an article of manufacture comprising: a base
comprising a membrane receiving portion; and a cover; and at least
one location in which the base and the cover are in communication
(at least one temporary or removable attachment between the base
and the cover, the base and the membrane, and/or the cover and the
membrane).
The present technology will be described in more detail below with
regard to the devices, compositions, articles of manufacture,
devices, systems and methods of utilizing each for the protection
of tissues, membranes or graft materials, for example, during
manufacture, processing, cryopreservation, storage, and
transport.
DESCRIPTION OF THE DRAWINGS
FIGS. 1A and 1B depict the base and the cover of an exemplary
support assembly as disclosed herein. FIG. 1A is a top view
depicting the base of the support assembly, and FIG. 1B is a top
view depicting the cover of the support assembly.
FIGS. 2A and 2B depict the base and the cover of another exemplary
support assembly as disclosed herein. FIG. 2A is a top view
depicting the base of the support assembly, and FIG. 2B is a top
view depicting the cover of the support assembly.
FIGS. 3A and 3B depict the base and the cover of another exemplary
support assembly as disclosed herein. FIG. 3A is a top view
depicting the base of the support assembly, and FIG. 3B is a top
view depicting the cover of the support assembly.
FIGS. 4A and 4B depict the base and the cover of another exemplary
support assembly as disclosed herein. FIG. 4A is a top view
depicting the base of the support assembly, and FIG. 4B is a top
view depicting the cover of the support assembly.
FIGS. 5A-5C schematically depict the assembly of a membrane product
package as disclosed herein. FIG. 5A is an exploded view of the
membrane product package, showing the relative orientation of the
base, the membrane, and the cover. FIG. 5B is a top view of the
base, showing the membrane positioned in engagement with the
product receiving portion of the base. FIG. 5C is a top view of the
membrane product package following positioning of the cover over
the membrane, thereby supporting the membrane between the cover and
the product receiving portion of the base. As shown, the membrane
can be attached to the base and the cover at a plurality of
attachment points as disclosed herein.
FIGS. 6A-6B depict an exemplary configuration of attachment points
on an exemplary support assembly as disclosed herein. FIG. 6A is a
top view depicting the attachment points on the base of the support
assembly, and FIG. 6B is a top view depicting the attachment points
on the cover of the support assembly.
FIGS. 7A-7B depict an exemplary configuration of attachment points
on another exemplary support assembly as disclosed herein. FIG. 7A
is a top view depicting the attachment points on the base of the
support assembly, and FIG. 7B is a top view depicting the
attachment points on the cover of the support assembly.
FIG. 8 is an isolated top view of a plurality of perforations of
the product receiving portion of a base, as disclosed herein.
FIG. 9 is an isolated top view of a product receiving portion
having a rough surface as disclosed herein.
FIGS. 10A-10D are schematic representations of experimental
perforation prototypes as described herein.
FIGS. 11A-11C are schematic representations of experimental
perforation patterns as described herein.
FIGS. 12A-12I are schematic representations of exemplary cautery
patterns for amniotic membrane products as described herein.
FIGS. 13A-13I are schematic representations of exemplary cautery
patterns for chorionic membrane products as described herein.
DETAILED DESCRIPTION
The present invention now will be described more fully hereinafter
with reference to the accompanying drawings, in which some, but not
all embodiments of the invention are shown. Indeed, this invention
may be embodied in many different forms and should not be construed
as limited to the embodiments set forth herein; rather, these
embodiments are provided so that this disclosure will satisfy
applicable legal requirements. Like numbers refer to like elements
throughout. It is to be understood that this invention is not
limited to the particular methodology and protocols described, as
such may vary. It is also to be understood that the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to limit the scope of the present
invention.
Many modifications and other embodiments of the invention set forth
herein will come to mind to one skilled in the art to which the
invention pertains having the benefit of the teachings presented in
the foregoing description and the associated drawings. Therefore,
it is to be understood that the invention is not to be limited to
the specific embodiments disclosed and that modifications and other
embodiments are intended to be included within the scope of the
appended claims. Although specific terms are employed herein, they
are used in a generic and descriptive sense only and not for
purposes of limitation.
As used herein the singular forms "a", "an", and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a cover" can include a plurality
of such covers, and so forth. All technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention belongs unless
clearly indicated otherwise.
Ranges can be expressed herein as from "about" one particular
value, and/or to "about" another particular value. When such a
range is expressed, another aspect includes from the one particular
value and/or to the other particular value. Similarly, when values
are expressed as approximations, by use of the antecedent "about,"
it will be understood that the particular value forms another
aspect. It will be further understood that the endpoints of each of
the ranges are significant both in relation to the other endpoint,
and independently of the other endpoint.
As used herein, the terms "optional" or "optionally" mean that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances where it does not.
The word "or" as used herein means any one member of a particular
list and also includes any combination of members of that list.
As used herein, the terms "product receiving portion" and "membrane
receiving portion" are used interchangeably, with it being
understood that both terms refer to a region of the base of a
support assembly or membrane product package as disclosed herein
that is configured to engage a surface of a biological product
(e.g., membrane) as disclosed herein and to cooperate with the
cover of the support assembly to support the biological product in
an operative position.
As used herein, the term "support assembly" generally refers to the
combination of a base and a cover as disclosed herein.
As used herein, the term "membrane product package" generally
refers to the combination of a base, a cover, and a membrane
positioned between the base and the cover, as further disclosed
herein.
As used herein, the term "traction-creating feature" refers to a
structural feature of the product receiving portion of a base as
disclosed herein that exhibits a high affinity for a biological
product (e.g., membrane) and/or that promotes adhesion, coupling,
or other operative contact between a biological product (e.g.,
membrane) and the product receiving portion as further disclosed
herein, which can produce surface traction between the top surface
of the product receiving portion of the base and the product (e.g.,
membrane) to prevent undesired movement of the product relative to
the base. Exemplary traction-creating features include a rough
surface; a plurality of perforations; a surface comprising a
plurality of channels; a surface comprising a plurality of grooves;
a surface comprising a plurality of indentations; or a surface
comprising a plurality of porations. Optionally, in use, it is
contemplated that the perforations, channels, grooves,
indentations, porations, and other void spaces can effectively
create a suction force that adheres the biological product (e.g.,
membrane) to the product receiving portion, whereas the rough
surfaces disclosed herein can mechanically (e.g., frictionally)
engage the bottom surface of the biological product (e.g.,
membrane) to resist movement of the product relative to the base.
Examples of such a "rough surface" include, for example and without
limitation, an abraded surface, a scratched surface, an uneven
surface, a gritty-type surface (yet, preferably free or
substantially free of loose particulate), or a bumpy surface, among
others. Optionally, it is contemplated that the product receiving
portion can comprise a combination of different rough surfaces that
cooperate to define the product receiving portion.
Overview
The present technology provides compositions, articles of
manufacture, devices, systems and methods of utilizing each for the
protection of tissues, membranes, or graft materials, for example,
during manufacture, processing, cryopreservation, storage and
transport to the health care provider/health care provider site.
Further, the present technology provides compositions, articles of
manufacture, devices, systems and methods of utilizing each for the
delivery or application of tissues, membranes, other biological
materials and grafts to a human or animal in need thereof. In
particular, the present technology provides compositions, articles
of manufacture, devices, systems and methods of utilizing each for
the treatment of wounds, tissue defects or membrane defects or
injuries in a human or animal. Further, the present technology
provides compositions, articles of manufacture, devices, systems
and methods of utilizing each for the preparation, storage,
transportation and delivery of tissue, membrane, grafts or other
biological products for others uses, including but not limited to
diagnostics, experimental testing and the like.
The present technology in at least some aspects and embodiments
comprises a device, composition, article of manufacture or system
(namely in the form of packaging) comprising at least a base and a
cover suitable for use with a biological membrane, tissue or graft
(or other biological material) that can support, stabilize and
protect such biological materials during manufacture, storage,
transportation and delivery/application (preferably by a health
care provider) to an end user (i.e., a human or animal patient) or
wound. Generally, the present technology also comprises at least
one location wherein the base and cover are in communication with
one another. Such communication between the base and the cover can
optionally be separate from the communication that the base and the
cover have with a tissue, membrane, graft or other biological
material as disclosed herein. Further, it should be appreciated by
those skilled in the art that the present technology also provides
devices, compositions, articles of manufacture and systems that can
be used multi-functionally as a carrier for a membrane, tissue,
other biological material or graft during the resultant packaging's
or packaging system's manufacture and storage, including for
example, during cryopreservation and thawing of the associated
membrane, tissue, graft, or other biological materials. Moreover,
the present technology provides at least one device, article of
manufacture, composition and/or system that allow for a desired
orientation (i.e., directionality, spatial arrangement, and/or
positioning) of the membrane, tissue, biological material or graft
material that is temporarily applied, supported, associated, or
affixed thereto in some manner or fashion.
Disclosed herein with reference to FIGS. 1A-8 is a support assembly
for supporting a biological product (e.g., membrane) 20 in an
operative position. In exemplary aspects, the support assembly can
comprise a base 30 and a cover 60.
In one aspect, and with reference to FIGS. 1A, 2A, 3A, 4A, and
5A-5C, the base 30 can have a longitudinal axis 32 and comprise a
product (e.g., membrane) receiving portion 40. In this aspect, the
product receiving portion 40 can have a top surface 42 and an
opposed bottom surface 44 that are spaced apart relative to a
vertical axis 34 that is perpendicular to the longitudinal axis 32
of the base 30. In exemplary aspects, the product receiving portion
40 of the base 30 can comprise at least one traction-creating
feature that is configured to promote surface traction between a
product (e.g., membrane) and the base. Optionally, in one exemplary
aspect, the traction-creating feature of the product receiving
portion 40 can be selected from the group consisting of (i) a rough
top surface 80 as further disclosed herein (see FIG. 9); and (ii) a
plurality of perforations 46 that extend between the top and bottom
surfaces 42, 44 of the product receiving portion. Thus, in some
optional aspects, the product receiving portion 40 can comprise a
rough top surface 80, while in other optional aspects, the product
receiving portion 40 can define a plurality of perforations 46.
In another aspect, and with reference to FIGS. 1B, 2B, 3B, 4B, and
5A, the cover 60 can have a longitudinal axis 62, a top surface 64,
and an opposed bottom surface 66. In this aspect, and as further
disclosed herein, the cover 60 can be configured for releasable
coupling (optionally, releasable attachment) to the base 30 in a
product-covering position. As shown in FIG. 5C, in the
product-covering position, the cover 60 can overlie the product
receiving portion 40 of the base 30 and any product (e.g.,
membrane) 20 positioned over the product receiving portion. In
exemplary aspects, the base 30 and the cover 60 are configured to
cooperate to support the biological product 20 in the operative
position. With reference to FIGS. 5A-5C, in the operative position,
the biological product 20 is positioned in engagement with at least
a portion of the top surface 42 of the product receiving portion 40
of the base 30 and at least a portion of the bottom surface 66 of
the cover 60. As further disclosed herein, it is contemplated that
the operative position can correspond to a desired orientation of
the product 20, such as, for example and without limitation, an
advantageous orientation for application of the product 20 to a
human or animal patient.
In a further aspect, the base 30 can further comprise a handling
portion 50 that is positioned adjacent to the product receiving
portion 40 relative to the longitudinal axis 32 of the base.
Optionally, in exemplary aspects, in the product-covering position,
the cover 60 does not overlap with the handling portion 50 of the
base 30. In further optional aspects, the handling portion 50 can
comprise a tab. In an exemplary aspect, the handling portion 50 of
the base 30 can have a longitudinal length 51 and a width, wherein
the product receiving portion 40 of the base has a longitudinal
length 41 and a width, and wherein the width of the product
receiving portion is equal to the width of the handling portion
(see FIG. 2A, showing the base 30 having a constant width 38).
Optionally, in some aspects, the longitudinal length 41 of the
product receiving portion 40 can be greater than the longitudinal
length 51 of the handling portion 50. Optionally, in other aspects,
the longitudinal length 41 of the product receiving portion 40 can
be less than the longitudinal length 51 of the handling portion 50.
In further optional aspects, the longitudinal length 41 of the
product receiving portion 40 can be substantially equal to the
longitudinal length 51 of the handling portion 50. As one will
appreciate, in combination, the longitudinal length 41 of the
product receiving portion 40 and the longitudinal length 51 of the
handling portion 50 can define a longitudinal length 36 of the base
30. However, in some optional aspects, and as further disclosed
herein, it is contemplated that the product receiving portion 40
can extend along substantially the entire longitudinal length 36 of
the base 30, in which case the longitudinal length 41 of the
product receiving portion will be substantially equal to the
longitudinal length of the base.
Optionally, in an additional aspect, in the product-covering
position, the longitudinal axis 62 of the cover 60 can be
positioned in substantial alignment with the longitudinal axis 32
of the base 30. In another aspect, the cover 60 can have a
longitudinal length 70 and a width 72. Optionally, in this aspect,
the longitudinal length 70 of the cover 60 can be substantially
equal to the longitudinal length 41 of the product receiving
portion 40. Optionally, it is further contemplated that the width
72 of the cover can be substantially equal to the width 38 of the
product receiving portion.
In a further aspect, and with reference to FIGS. 1A-1B, the cover
60 can have a plurality of corners 68. Optionally, in this aspect,
at least one of the corners 68 of the cover is rounded. In
exemplary aspects, it is contemplated that the cover 60 can have
four rounded corners 68. However, it is contemplated that the
corners 68 can have other sharp or non-sharp profiles, such, as for
example and without limitation, a beveled profile. In further
exemplary aspects, it is contemplated that the product receiving
portion 40 of the base 30 can have two rounded corners 45. In these
aspects, it is contemplated that, in the product-covering position,
two rounded corners 68 of the cover 60 can overlie the two rounded
corners 45 of the product receiving portion 40 of the base 30. It
is further contemplated that the handling portion 50 of the base 30
can have two corners (optionally, rounded corners) 52 that are
positioned in opposition to the corners 45 defined by the product
receiving portion 40.
In exemplary aspects, the plurality of perforations 46 of the
product receiving portion 40 of the base 30 can be substantially
evenly distributed throughout the product receiving portion.
In further exemplary aspects, the plurality of perforations 46 of
the product receiving portion 40 of the base 30 can be randomly
distributed throughout the product receiving portion.
In an additional aspect, and with reference to FIG. 8, each
perforation 46 of the plurality of perforations can have a
respective diameter 47. Optionally, in exemplary aspects, the
diameter 47 of each perforation 46 can range from about 0.1 mm to
about 5 mm. Optionally, it is contemplated that the perforations 46
can have substantially equal diameters. However, it is further
contemplated that at least one perforation 46 of the plurality of
perforations can have a diameter 47 that is substantially different
than the diameter of at least one other perforation.
In another aspect, and with reference to FIG. 8, each perforation
46 of the plurality of perforations can have a respective center
point 48. Optionally, in this aspect, it is contemplated that the
center points 48 of neighboring perforations 46 can be spaced apart
by a distance 49 ranging from about 0.35 mm to about 10 mm.
In exemplary aspects, and with reference to FIGS. 5A-7B, the
disclosed support assembly (base 30 and cover 60) can be provided
as part of a membrane product package 100. In these aspects, in
addition to the support assembly, the membrane product package 100
can comprise a membrane 20 positioned in an operative position
between the product receiving portion 40 of the base 30 and the
cover 60 (relative to the vertical axis 34). As further disclosed
herein, the membrane 20 can have an upper surface 26 and an opposed
lower surface 28. It is contemplated that the membrane 20 can be
positioned in engagement with at least a portion of the top surface
42 of the product receiving portion 40 of the base 30 and at least
a portion of the bottom surface 66 of the cover 60.
In one aspect, the lower surface 28 of the membrane 20 can be
attached to the top surface 42 of the product receiving portion 40
of the base 30 at at least one attachment point 22. Optionally, in
exemplary aspects, the lower surface 28 of the membrane 20 can be
attached to the top surface 42 of the product receiving portion 40
of the base 30 at at least three attachment points 22. Optionally,
in further exemplary aspects, the lower surface 28 of the membrane
20 can be attached to the top surface 42 of the product receiving
portion 40 of the base 30 at at least five attachment points 22.
Optionally, it is contemplated that the attachment points 22 can be
cauterization points (where the product receiving portion 40 and
the membrane 20 are cauterized together).
In one aspect, the cover 60 can be attached to the upper surface 26
of the membrane 20 at at least one attachment point 24. Optionally,
in exemplary aspects, the cover 60 can be attached to the upper
surface 26 of the membrane 20 at at least two attachment points 24.
Optionally, in further exemplary aspects, the cover 60 can be
attached to the upper surface 26 of the membrane 20 at at least
three attachment points 24. Optionally, it is contemplated that the
attachment points 24 can be cauterization points (where the cover
60 and the membrane 20 are cauterized together).
Optionally, at least one attachment point 24 where the cover 60 is
attached to the membrane 20 can overlie and/or substantially
correspond to an attachment point 22 where the product receiving
portion 40 of the base 30 is attached to the membrane 20. At these
attachment points, it is contemplated that the base 30, the
membrane 20, and the cover 60 can be secured together.
In addition to, or alternatively to, the attachment of the membrane
20 to the product receiving portion 40 and/or the cover 60, the top
surface of the product receiving portion of the base can be
directly attached to the cover at at least one attachment point.
Optionally, in exemplary aspects, the top surface 42 of the product
receiving portion 40 of the base 30 can be attached to the cover 60
at at least three attachment points. In these arrangements, it is
contemplated that the membrane can have a length and a width that
are less than the longitudinal length and the width of the product
receiving portion 40 and the cover 60 to thereby define a
peripheral edge region around the membrane 20, and at least one
attachment point (where the product receiving portion is directly
attached to the cover) can be positioned in the peripheral edge
region and spaced from an outer edge of the membrane.
In exemplary aspects, the membrane 20 can be a natural membrane,
such as, for example and without limitation, a placental tissue
product. Optionally, in one aspect, the membrane 20 can be a
chorionic membrane product. Optionally, in a further aspect, the
membrane can be an amniotic membrane product.
In further exemplary aspects, the membrane 20 can be a synthetic
membrane.
In still further exemplary aspects, it is contemplated that the
membrane 20 and the top surface 42 of the product receiving portion
40 of the base 30 can have sufficient surface traction to maintain
the membrane in the operative position following removal of the
cover 60 from the base.
In additional exemplary aspects, the membrane 20 and the top
surface 42 of the product receiving portion 40 of the base 30 can
have a first surface traction. In these aspects, it is contemplated
that the membrane 20 and the cover 60 can have a second surface
traction that is lower than (less than) the first surface
traction.
In exemplary aspects, and with reference to FIGS. 5A-5C, a method
of producing a membrane product package as disclosed herein is
provided. In these aspects, the method can comprise positioning a
membrane in an operative position between the product receiving
portion of the base and the cover of the support assembly. In these
aspects, the membrane can be positioned in engagement with at least
a portion of the top surface of the product receiving portion of
the base and at least a portion of the bottom surface of the
cover.
Optionally, the step of positioning the membrane in the operative
position can comprise attaching the membrane to the top surface of
the product receiving portion at a plurality of attachment points
as disclosed herein. It is further contemplated that the step of
positioning the membrane in the operative position can further
comprise attaching the membrane to the cover at a plurality of
attachments points as disclosed herein.
Optionally, in further aspects, the method can further comprise
positioning the base, the membrane, and the cover within a
cryopreservation solution. In these aspects, when the
traction-creating feature of the product receiving portion of the
base comprises a plurality of perforations as disclosed herein, the
plurality of perforations can provide contact between the membrane
and the cryopreservation solution sufficient to cryopreserve the
membrane.
In additional exemplary aspects, a method of applying a membrane is
disclosed. In these aspects, the method can comprise removing the
cover from a membrane product package as disclosed herein to expose
a top surface of the membrane. In another aspect, the method can
further comprise disengaging the membrane from the top surface of
the product receiving portion of the base. In a further aspect, the
method can further comprise selectively applying the membrane to a
desired location on a human or animal patient.
In further exemplary aspects, a kit for repairing a tissue defect
is disclosed. In these aspects, the kit can comprise a membrane
product package 100 as disclosed herein. In additional optional
aspects, the kit can further comprise a container (e.g., a bag)
that encloses the membrane product package. In these aspects, the
container can be selectively opened to provide access to the
membrane product package. In further optional aspects, the kit can
further comprise instructions for applying the membrane of the
membrane product package to repair the tissue defect. In still
further optional aspects, the kit can further comprise a
cryopreservation solution. Optionally, in other aspects, the kit
can further comprise a basin configured to receive the membrane
product package. In these aspects, it is contemplated that the
basin can serve as a wash basin and/or thawing basin for the
membrane product package. In still another aspect, the kit can
optionally comprise scissors. In yet another optional aspect, the
kit can comprise tweezers.
Further exemplary aspects of the disclosed concepts are provided in
the following sections of the specification.
The Base
a. Product/Membrane Receiving Portion
As shown in FIGS. 1A, 2A, 3A, 5A-5C, 6A, 7A, and 9, the base 30 of
the presently described technology comprises at least one receiving
portion 40. The receiving portion 40 is capable of receiving a
biological product, material, or composition 20. Such materials or
compositions may include, for example, membranes, tissues, graft
materials, and the like. Throughout the remainder of the
specification and appended claims, the biological product will
generally be referred to as a "membrane," and the receiving portion
40 shall be referred to interchangeably as either the "product
receiving portion" or the "membrane receiving portion." It should
be appreciated by those skilled in the art, however, that the term
encompasses and contemplates the receipt and engagement of other
biological materials such as tissues, other biological materials
and grafts. The membrane receiving portion 40 is a portion of the
base 30 (of the present technology) that contacts the membrane 20.
The membrane receiving portion 40 of the present technology also
can comprise at least one traction-creating feature. As further
disclosed herein, the traction-creating feature provides a surface
which, when in contact with the membrane 20, provides sufficient
surface traction such that the membrane remains sufficiently but
temporarily attached to the base 30 and prevents, for example,
curling or detachment of the membrane during manufacture, storage,
transport and handling prior to final removal from the packaging or
packaging system and application to an end user or for an end use
application (e.g., wound treatment, diagnostic testing or
experimental/analytical laboratory usages). Thus, the
traction-creating feature (e.g., a structured surface) provides
sufficient support, attachment/connection and/or stabilization of
the membrane 20 in conjunction with the base 30 when applied
thereto. This is unexpected since the packaging device,
composition, article of manufacture or system of the present
technology itself (e.g., the support assembly disclosed herein),
not the membrane, tissue or graft material, provides such outcomes,
especially during each of the phases of preparing, storing,
transporting, handling, and administering of the end product. It is
also unexpected that the presently described technology can provide
such outcomes while still allowing the end user to size, shape and
finally apply the end product to the patient (human or animal) in a
convenient manner without significant waste, destruction, damage,
injury, or other negative outcome to the membrane to be
applied.
As further described herein, the traction-creating features may be
any suitable surface feature that provides the necessary surface
traction when in contact with the membrane, tissue, biological
material or graft material. The surface traction necessary to
maintain contact with the membrane, tissue, or graft (or other
biological material to be delivered) will depend upon the
composition of the membrane, tissue, graft or other biological
material to be applied, temporarily affixed or attached in some
non-permanent manner to the membrane receiving portion 40. The type
of material used to form or make the base 30 will also affect the
surface traction necessary to maintain contact between the
membrane, tissue, graft or other biological material with the
traction-creating feature of the membrane receiving portion of the
base. Thus, it should be appreciated by those skilled in the art
that the surface traction depends on a number of factors, including
the type of base material selected, the traction-creating features
of the membrane receiving portion (including, for example, the
perforation, channel, groove, indentation pattern, or other pattern
or surface type selected/desired), and the type of membrane. In at
least one embodiment of the present technology, a sufficient
surface traction is characterized by a package (i.e., a device, a
composition, an article of manufacture) or packaging system of the
present technology having the following features: 1) at least one
membrane that does not spontaneously detach from the base (or a
selected portion, segment or part of the base) when submerged in a
medium (e.g., a biological medium, including a biological solution)
and 2) the ability of the membrane to slide from the base without
ripping, tearing or damage to the membrane when removed from the
packaging or packaging system and then subsequently applied to the
wound or tissue defect of the human or animal to be treated.
Other suitable methods of testing surface traction sufficient for
the purposes of practicing the present technology may be determined
by equipment and methodology known conventionally. For example, a
sufficient surface traction can be determined instrumentally via an
Instron measurement device commercially available from Instron,
Incorporated of Norwood, Mass. (a manufacturer of surface traction
testing equipment designed to evaluate the mechanical properties of
materials and components (www.instron.us/)). Surface traction in
some instances is also known as sliding frictional force. Sliding
frictional force is understood and can be determined by one skilled
in the art, for example, see Sliding Friction: Physical Principles
and Applications (NanoScience and Technology) by Bo Persson (Jun.
21, 2000) 2.sup.nd edition, Springer (ISBN-10: 3540671927 ISBN-13:
978-3540671923), and Advances in Soft Matter Mechanics by Shaofan
Li, and Bohua Sun (2012), (ISBN: 978-3-642-19372-9 (Print)
978-3-642-19373-6 (Online)), incorporated by reference in their
entireties.
Traction-creating features (e.g., structured surfaces) can include,
but are not limited to, for example, a rough surface (e.g., an
uneven surface, a scratched surface, and the like), a surface
comprising a plurality of perforations or porations, a surface
comprising a plurality of channels (a channeled surface), a surface
comprising a plurality of grooves (a grooved surface), or a surface
comprising a plurality of indentations (an indented surface), among
others. Combinations of such surfaces can also be utilized. In some
instances, the traction-creating features comprise at least one
perforation, at least one channel, at least one groove, at least
one indentation, and in some instances, the at least one
perforation, at least one channel, at least one groove or at least
one indentation is a complex pattern or design. In one exemplary
aspect, the traction-creating feature can comprise a
sandpaper-roughened surface.
Further, a variety of patterns, designs or shapes of various
traction-creating features (e.g., structured surfaces) can also be
utilized in the practice of the presently described technology. For
example, the traction-creating feature (e.g., structured surface)
may be a circular pattern of perforations, alternatively, a square
pattern of perforations and the like. Further designs, shapes, and
patterns suitable for use in the practice of the present technology
are illustrated in FIGS. 1A-9. It should be appreciated by those
skilled in the art that any pattern, design or shape may be
utilized as long as a sufficient surface traction between the
traction-creating feature and the membrane, tissue, graft or other
biological material can be achieved such that the membrane, tissue,
graft, or other biological material is stable and supported during
manufacture, storage, transport and handling prior to final
application of the membrane to the end user (or for its use in an
end application such as diagnostic or analytical testing). Yet, the
sufficient surface traction (and associated attraction, affinity,
and/or adhesion) is only temporary such that the end user can
remove the membrane, tissue, graft, or other biological material
for final application to the human or animal patient (or for final
end application usage) without significant negative outcomes such
as curling, self-adherence, damage, injury and the like. In some
embodiments of the present technology, the traction-creating
feature (e.g., structured surface) can be irregular, continuous,
discontinuous, symmetrical, dyssymmetrical in design, shape or
pattern, or comprise a combination of different types of
traction-creating features (e.g., structured surfaces).
During storage, such as cryopreservation storage, it should be
appreciated by those skilled in the art that the traction-creating
feature (e.g., structured surface) of the membrane receiving
portion provides enough or sufficient surface traction such that
the membrane is able to temporarily adhere or remain attached or
connected to the base and is not significantly dislodged from the
base when a cryopreservation solution is introduced into the
packaging device, composition, article of manufacture or system of
the present technology. It has been surprisingly found that the
present technology allows the membrane, tissue, graft or other
biological material to remain temporarily adhered, attached or
connected to the membrane receiving proportion sufficient to
withstand shear fluid force that is typically produced when a
cryopreservation solution or other solution or liquid material is
introduced into the packaging device, article of manufacture,
composition, or system. The fluid may be introduced, for example,
into a bag or other suitable container that can be part of the
device, composition, article of manufacture, or system of the
present technology that may hold the base/membrane/cover
configuration therein or thereupon. Again, it should be appreciated
by those skilled in the art that the present technology via the
traction-creating feature (e.g., structured surface) of the
membrane receiving portion of the base (alone or alternatively in
combination or further communication with the cover), provides
sufficient surface traction with the membrane, tissue, graft or
other biological material to stabilize, support, and to temporarily
hold in place that membrane while withstanding freezing procedures,
shipping, storage, handling and thawing procedures prior to final
application to a wound or tissue defect.
The membrane receiving portion of the present technology may span
the entire length of the base or may span only a portion, section,
part or segment of the base. In some aspects, for example, the
membrane receiving portion can span at least 30% of the length of
the base. In other aspects, the membrane receiving portion can span
at least 40% of the length of the base. In additional aspects, the
membrane receiving portion can span at least 50% of the length of
the base 30. In still further exemplary aspects, the membrane
receiving portion can span at least 60% of the length of the base
30. In still further exemplary aspects, the membrane receiving
portion can span at least 70% of the length of the base 30. In
still further exemplary aspects, the membrane receiving portion can
span at least 80% of the length of the base 30. In still further
exemplary aspects, the membrane receiving portion can span at least
90% of the length of the base 30. In still further exemplary
aspects, the membrane receiving portion can span at least 95% of
the length of the base 30. In some embodiments, the membrane
receiving portion spans about 95% of the length of the base. In
other embodiments, for example, the membrane receiving portion
spans about 30%, about 35%, about 40%, about 45%, about 50%, about
55%, about 60%, about 65%, about 70%, about 75%, about 80%, about
85%, about 90%, about 95%, about 98%, about 99%, or about 100% of
the length of the base, and it should be appreciated that such
spans can include increments and percentages in between (for
example, 70%, 71%, 71.5%, 72%, 72.5%, 73%, among others).
The term "plurality" when used to describe a plurality of
perforations, a plurality of channels, a plurality of grooves, or a
plurality of indentations, for example, refers to a sufficient
number of such perforations, channels, grooves, indentations and
the like being distributed throughout the membrane receiving
portion so as to provide a sufficient tension or surface traction
for the graft, tissue, membrane or other biological material to
temporarily adhere, connect or attach to the base and withstand the
processing and handling during manufacture, transport, storage,
handling and final application to a wound or tissue defect.
b. Perforation of the Membrane Receiving Portion
In some embodiments of the present technology, and with reference
to FIGS. 1A, 2A, 3A, and 5A-5C, the membrane receiving portion 40
comprises a plurality of perforations 46 and/or porations. In some
embodiments, the membrane receiving portion 40 may comprise at
least one perforation 46. The at least one perforation may be a
complex pattern or design. Optionally, each perforation 46 can be a
small hole within a material (e.g., the membrane receiving portion
of the base). It is contemplated that the perforations 46 can be
formed by any suitable means in the art. Continuous perforated or
microperforated sheets for use in the practice of the present
technology may be prepared by any conventional method known in the
art utilizing a substrate sufficient and consistent with the
practice and intentions of the presently described technology to
temporarily adhere, attach, or connect the membrane 20 while
providing support as well. Suitable means for perforating the base
30 (or membrane receiving portion 40 of the base) can include, but
are not limited to, mechanical perforation devices such as suitably
arranged punching machines, thermal or ultraviolet lasers operating
in a desired frequency band, rotary pinned perforation rollers, a
die and punch set, a vacuum, a needle or water jet perforation
device or system, hot pins, an embossing device or system and any
combinations thereof, among others.
The plurality of perforations (or porations) 46 may also comprise a
shape, design, or pattern or may be randomly orientated within the
membrane receiving portion 40 of the base 30. In still further
embodiments, the plurality of perforations 46 are evenly
distributed across the membrane receiving portion 40. The
perforations 46 may be simply ordered or may be arranged according
to complex sequences. The pattern of the plurality of perforations
46 may comprise, for example, a grid pattern (e.g., a series of
rows and columns). In some embodiments of the present technology,
the size of each perforation 46 can be from about 0.1 mm to about 5
mm. Suitably, the perforations 46 can have a diameter (maximum
width) of about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm,
about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1 mm,
about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5
mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about
2.0 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm,
about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9
mm, about 3.0 mm, 3.1 mm, about 3.2 mm, about 3.3 mm, about 3.4 mm,
about 3.5 mm, about 3.6 mm, about 3.7 mm, about 3.8 mm, about 3.9
mm, about 4.0 mm, about 4.1 mm, about 4.2 mm, about 4.3 mm, about
4.4 mm, about 4.5 mm, about 4.6 mm, about 4.7 mm, 4.8 mm, about 4.9
mm and about 5.0 mm and any increments between, including
increments from between about 0.01 mm to about 0.1 mm. In further
aspects and embodiments of the present technology, the perforation
size can preferably range from about 0.1 mm to about 20.3 mm, and
spacing can be about 0.35 mm to about 20 mm center to center.
Optionally, in some exemplary aspects, the diameter of at least one
perforation 46 can be different (less than or greater than) the
diameter of at least one other perforation of the plurality of
perforations.
The number and size of the perforations 46 depends upon the
material or substrate of which the membrane receiving portion 46 is
made from, the type of membrane 20, tissue, graft or other
biological material adhered, attached, connected or associated (all
temporarily) with the membrane receiving portion, and the surface
traction that is sufficient to maintain the membrane, tissue, graft
and/or other biological material temporarily on, onto, connected
to, attached to, adhered to and the like to the base 30 during
processing, storing, transporting, and handling. Additionally, the
perforations (or porations) 46 may be any geometrical or
non-geometrical shape. Suitable shapes include, but are not limited
to, circular, oval, rectangular, square, diamond, trapezoidal,
star, hexagonal, octagonal, semi-circular, crescent, ellipse or a
combination thereof. Perforations (or porations) 46 may also be a
section or part of a shape, such as a half star or half crescent.
It should be understood by those skilled in the art that one or
more shapes may be used in any combination as well.
The center-to-center distance 49 between adjacent (neighboring)
perforations (or porations) 46 on the base 30 (or membrane
receiving portion 40 of the base) depends upon the size and number
of perforations (or porations) 46 that can be distributed
throughout the area selected (for example, the size of the membrane
receiving portion) and the overall selected size of the base,
itself. The size and number of perforations (or porations) 46
permissible in the base 30 (or membrane receiving portion 40 of the
base), in turn, depend upon the effect of the same upon the
physical properties of the base, the cover 60, and the stabilizing,
temporarily connective and protective functions served by the base
and structure of the perforations with respect to the associated
membrane 20, tissue, graft and/or other biological material(s). For
example, the distance 49 between perforations 46 as measured from
the center of one perforation to the center of another perforation
may be from about 0.3 to about 10 mm, alternatively from about 0.35
mm to about 10 mm, alternatively from about 0.35 mm to about 5 mm,
alternatively from about 1 mm to about 5 mm, alternatively from
about 4 mm to about 10 mm, and any increments and distances in
between, including increments from about 0.01 mm to about 0.1 mm.
Preferably, the distance 49 between perforations (or porations) 46
is from about 1 mm to about 10 mm, more preferably about 3 mm to
about 5 mm, such as 3 mm or 4 mm.
While not wanting to be bound by any particular theory, it has been
observed and discovered in the practice of the present technology
that the smaller the membrane 20 (tissue, graft, or other
biological material(s)) to be attached to the base 30 (or membrane
receiving portion 40 of the base), the smaller the perforations (or
porations) 46 can be within the base (or membrane receiving portion
of the base). Conversely, the larger the membrane 20 to be attached
to the base 30 (or membrane receiving portion 40 of the base),
larger perforations (or porations) 46 can be utilized and the
farther apart the perforations (or porations) can be spaced as
well. For example, for a 7.5 cm.times.15 cm (7.5 cm length.times.15
cm width) membrane, the perforations may be about 5 mm in diameter
and about 10 mm apart (as measured center to center). For a
membrane that is approximately 1.5 cm.times.2 cm, the perforations
may be about 1 mm diameter and about 4 mm apart center to center.
In some embodiments of the present technology, for a membrane that
is approximately 5 cm.times.5 cm or 3 cm.times.4 cm, the
perforations may be about 1 mm diameter and about 4 mm apart center
to center. In other embodiments, for an approximately 2 cm.times.3
cm membrane, the perforations may be about 1 mm diameter and about
3 mm apart center to center. It should be appreciated by those
skilled in the art that such examples are for illustrative purposes
only and are not to be considered exhaustive. In some instances,
not to be bound by any particular theory, for membrane sizes over
100 cm.sup.2 the size of perforations may be increased up to five
fold and the distance between the perforations may be increased by
2-3 fold.
Preferably, the method of forming perforations (or porations)
should not create microparticles or other impurities or
contaminants (or pollutants) that are permanently stained on the
base and cannot be removed, or would otherwise be detrimental to
the membrane. Further, the perforated (or porated) base (or
membrane receiving portion thereof) should be free of oil or other
chemicals, materials, impurities, pollutants, contaminants or
substances that may interfere with the performance of the base and
the membrane receiving portion according to the practice of the
present technology, or would otherwise not be biocompatible or
would be detrimental to the membrane. Moreover, the base and
membrane receiving portion (however modified, for example, via
perforating, grooving, channeling, etc.) should be able to maintain
a sufficient cleanliness to protect and/or maintain the cellular
viability of the associated membrane, tissue, graft and/or other
biological materials temporarily associated therewith, maintain
integrity of the associated membrane, tissue, graft and/or other
biological materials temporarily associated therewith, and/or
provide safety for the human or animal being treated (e.g., comply
with safety regulations). In doing so, a detrimental response by a
patient to the membrane, tissue, graft and/or other biological
material(s) can be reduced or prevented when provided to patients,
(e.g., when applied to or transplanted on or within various areas
of a patient(s) such as a wound or tissue defect).
c. Grooves/Channels/Indentations, etc.
In some embodiments of the present technology, the membrane
receiving portion 40 may comprise a plurality of grooves. In some
embodiments, the membrane receiving portion 40 may comprise at
least one groove, wherein in some instances, the at least one
groove is a complex pattern or shape. The grooves can span the
entire length of the membrane receiving portion or any segment,
portion, or part thereof. The grooves may be discontinuous or
continuous over the entire length or portion (or segment or part)
of the membrane receiving portion of the base. The grooves can be
orientated in parallel or in a perpendicular conformation, or a
combination thereof. The grooves may be evenly distributed or
randomly distributed over the respective length, segment, portion
or part of the membrane receiving portion. The grooves should cover
a sufficient area of the membrane receiving portion to provide a
sufficient surface traction such that the membrane, tissue, graft
and/or other biological material associated therewith temporarily
adheres, connects, or attaches to the membrane receiving portion
(or base) for purposes of stabilization, temporary connection and
protection during manufacture, handling, storage, transport and
final application or usage.
In other embodiments of the present technology, the membrane
receiving portion 40 may comprise a plurality of channels. The
channels may be discontinuous or continuous over the entire length
of the membrane receiving portion, or alternatively a portion,
part, or segment thereof. The channels may be evenly distributed or
randomly over the membrane receiving portion. The channels can be
orientated in a parallel conformation to one another, a
perpendicular conformation to one another, or a combination
thereof. The channels preferably cover a sufficient area of the
membrane receiving portion of the base to provide sufficient
surface traction such that the membrane temporarily adheres,
connects or attaches to the membrane receiving portion during
manufacturing, handling, storage and final application or
usage.
In still other embodiments, the membrane receiving portion 40 of
the present technology can comprise a plurality of indentations.
The indentations may be evenly distributed over the entire length,
portion or segment of the membrane receiving portion of the base.
The channels may be randomly or evenly distributed over the entire
length, portion or segment of the membrane receiving portion. The
indentations may also be arranged in rows and other patterns,
designs or configurations. The rows may be parallel or intersecting
over the entire (or alternatively a portion, part, or segment of
the) length, of the membrane receiving portion of the base. The
indentations should cover a sufficient area of the membrane
receiving portion of the base to provide sufficient surface
traction such that a membrane, tissue, graft, or other biological
material(s) sufficiently but temporarily adheres, connects or
attaches to the base during manufacturing, handling, storage,
transit and final application or usage.
d. The Membrane Receiving Portion Surface
In some embodiments of the present technology, and with reference
to FIG. 9, the membrane receiving portion 40 of the base is a rough
surface 80, preferably a rough plastic surface. However, it should
be appreciated that other materials suitable for use to practice
the presently described technology are also envisaged. Suitable
means of making a rough surface include, but are not limited to,
sanding, chemical alteration, 3-D printing, abrasive blasting, and
other methods known to one skilled in the art. The rough surface 80
should provide a sufficient surface traction such that the
membrane, tissue, graft, or other biological material(s)
temporarily adheres, connects, or attaches to the membrane
receiving portion of the base during manufacturing, handling,
storage, transit and final application or usage, but not too
strongly so as to not be able to be easily removed and applied
(e.g., to a wound or tissue defect or for use in a further
procedure).
In other embodiments, the membrane receiving portion 40 may exhibit
a scratched surface. Again, the scratched surface should provide a
sufficient surface traction such that the membrane, tissue, graft,
or other biological material(s) temporarily adheres, connects, or
attaches to the membrane receiving portion of the base during
handling, storage, transit and application, but not too strongly so
as to not be able to be easily removed and applied (e.g., to a
wound or tissue defect or for use in a further procedure).
e. Handling Portion
In some aspects and embodiments of the present technology, and with
reference to FIGS. 1A, 2A, 3A, 5A-5C, 6A, 7A, and 9, the base 30
further comprises at least one handling portion 50. The handling
portion 50 may be, for example, adjacent to the membrane receiving
portion 40. The handling portion 50 provides a region of the
device, system, article of manufacture, or composition of the
present technology that can be handled or operated by an individual
without causing damage, injury to or significant waste,
disorientation, or negative outcomes to the membrane 20 (tissue,
graft, or biological material(s)) applied thereto. This reduces
direct contact with the membrane 20 and a handler, which reduces
damage to the membrane (among other things) and maintains, in the
case of living membranes, cellular viability, and other attendant
beneficial biological properties and functions when applied to a
patient or utilized in other therapeutic, diagnostic, analytical
and/or experimental laboratory manners.
In still further embodiments, and with reference to FIGS. 6A and
7A, the handling portion 50 can also contain a marker, label or
designation 55 for orientation and/or application. This allows for
the indication of the directionality, spatial arrangement or proper
application of a membrane 20 (e.g., tissue, graft, or other
biological materials) temporarily applied to the membrane receiving
portion 40 of the base 50, which can be maintained throughout
preparation, cryopreservation, storage, transport, thawing and
final application to a patient or other usage. The marker 55 for
orientation may be any symbol that can indicate a proper
orientation, proper application or usage, and/or directionality.
For example, the marker 55 can be a name, a trade name for the
packaging product (kit or system), an arrow, at least one word or a
letter, a directional symbol, or other suitable alternatives. To
illustrate, suitable letters that require orientation, for example,
include but are not limited to B, C, D, E, F, G, J, K, N, P, Q, R,
S, and/or Z. To further illustrate, suitable orientation markers 55
may be the name of the product, for example Grafix PRIME.RTM. or
Grafix CORE.RTM. owned by Osiris Therapeutics, Inc. of Columbia,
MID. In other embodiments, the marker 55 may be a word or phrase,
for example "top," "this side up," face," "forward," "product,"
"handle side", "keep this side up." One of skill in the art shall
appreciate additional alternatives that can provide the
orientation, proper application, and/or directionality of the
device, composition, article of manufacture, or system of the
present technology. In some embodiments, the label or marking 55
may be a colored letter, square, block or edge. In doing so, the
device, composition, article of manufacture, or system of the
present technology provides the advantage of informing the handler
of the proper orientation placement of at least one membrane 20
(e.g., tissue, graft, or other biological material) on, onto, or
upon the membrane receiving portion 40 of the base 30. Further, the
marker 55 for orientation also provides information to a handler
(e.g., a health care provider) regarding the proper orientation of
the device, composition, article of manufacture, or system of the
present technology (e.g., the support assembly or membrane product
package 100 disclosed herein) prior to the membrane, tissue, graft,
or other biological material(s) being applied to the patient. Thus,
it should be appreciated by those skilled in the art that any
shape, symbol, color, design, pattern and the like may be utilized
and are envisaged in the practice of this aspect and embodiments of
the present technology.
Optionally, in additional embodiments, the cover 60 comprises at
least one handling portion. The handling portion of the cover 60
may also contain a marker for orientation and/or labeling of the
product as described herein. The handling portion of the cover 60
may also be used for removal of the cover) during the end
application process (e.g., to a patient or usage during a
diagnostic procedure, laboratory analysis or some other usage). In
some of these embodiments, the handling portion can be a grip. The
grip may be used to remove the cover that is temporarily adhered,
connected or attached from the membrane, tissue, graft, or other
biological material(s) and base.
In other embodiments, both the cover 60 and the base 30 both
separately comprise at least one handling portion or can jointly
form at least one handling portion. In still further embodiments,
the base 30 may comprise a first handling portion while the cover
60 may comprise a second handling portion that may operate
separately or may work cooperatively with the first handling
portion. In other embodiments, the first handling portion and the
second handling portion are in communication with each other. The
communication is preferably temporary but sufficient to maintain
communication during manufacture, handling, transport and prior to
final application or usage. For example, in some embodiments, the
second handling portion can overlap at least a part, portion, or
segment of the first handling portion.
Additionally, it should also be appreciated that the respective
handling portion (of the base 30 or the cover 60) can be the entire
width of the cover and/or the base. Alternatively, the handling
portion may comprise only a portion, segment, or part of the width
of the cover and/or base. A portion, segment, or part of the width
may be about 10%, about 20%, about 30%, about 40%, about 50%, about
60%, about 70%, about 80%, about 90%, about 95% of the width, and
any percentage or width in between. The handling portion should be
sufficiently sized so as to provide a region of the cover and/or
base to allow a handler to safely handle the device, composition,
article of manufacture or system of the present technology without
causing injury or damage to the membrane, tissue, graft, or other
biological material(s) associated therewith. Further, the handling
portion should be sufficiently sized so as to provide ease of
handling by the handler. Moreover, the handling portion should be
sufficiently shaped so as to provide easy of use while providing a
more comfortable handling, such as through the prevention of cuts
upon the handlers fingers during handling that can result if the
edges of the handling portion are not smoothed (e.g., rounded or
sanded, etc.).
In some embodiments of the present technology, the handling portion
is from about 1 cm to about 5 cm wide and the same length as the
membrane receiving portion 40 of the base 30. Sizing of the
handling portion depends on the size of the membrane receiving
portion of the base, and the handle portion in some optional
embodiments does not exceed the size of the membrane receiving
portion of the base. In other embodiments, the handling portion is
about 1 cm wide, preferably about 2 cm wide, alternatively about
2.5 cm wide, alternatively about 3 cm wide, and spans the entire
length or a portion, part, or segment of the entire length of the
membrane receiving portion. In still further embodiments, the
handling portion is preferably at least about 1 cm wide.
The Cover
With reference to FIGS. 1B, 2B, 3B, 4B, 5A, 5C, 6B, and 7B, the
cover 60 of the compositions, devices, articles of manufacture or
systems of the present technology (e.g., the support assembly and
the membrane product package 100) can optionally be the same size
as the base 30. Alternatively, in other embodiments, the cover 60
is substantially the same size as the membrane receiving portion 40
of the base 30. Preferably, the cover 60 is of a sufficient size to
protect a membrane 20 (e.g., tissue, graft or other biological
material(s) that is temporarily attached, connected, or adhered to
the cover and/or the membrane receiving portion of the base) from
shear forces and stresses produced or faced during processing,
storage, transport, handling and final application or usage. In the
various embodiments of the present technology, the cover 60 can
optionally be a single piece of suitable biocompatible substrate.
In some embodiments, the substrate is a biocompatible plastic,
biopolymer, biocopolymer or other biocompatible material that does
not significantly injure, damage, contaminate or otherwise harm the
associated membrane of the present technology.
Shape/Size/Make-Up of the Cover and Base
In some embodiments of the present technology, the base 30 can
exhibit a shape that comprises non-sharp corners 45, 52.
Optionally, the corners of the base 30 can be rounded. In still
further embodiments, the cover 60 can comprise non-sharp corners
68. In some preferred embodiments, the corners 45, 52, 68 of the
cover and/or base are rounded. Non-sharp corners are preferred for
safety and handling of the device, system, article of manufacture,
or composition of the present technology during manufacturing,
storage, transport, or application/usage, and also to prevent
tearing or puncturing of the temporarily associated membrane,
tissue, graft, or other biological material(s) during removal from
the base and/or cover. It should be appreciated that the base and
cover may be of any desired geometrical shape. In some preferred
embodiments, the base and cover are squares or rectangles,
preferably squares or rectangles with rounded corners. However, it
is further contemplated that the cover and/or base can have a round
shape (e.g., a circular or elliptical shape).
It should also be appreciated by those skilled in the art that the
device, article of manufacture, composition, or system (e.g., the
support assembly or the membrane product package 100) can exhibit a
varying size. In some embodiments, the size of the device, article
of manufacture, composition or system can be a customizable size
for a particular application which is chosen by the manufacturer or
the handler prior to end application or usage. For example, in some
embodiments, the size (longitudinal length.times.width) can be
about 1 cm.times.1 cm, about 1.5 cm.times.2 cm, about 1.5
cm.times.1.5 cm, about 2 cm.times.2 cm, about 2.5 cm.times.2.5 cm,
about 2 cm.times.3 cm, about 2 cm.times.4 cm, about 2 cm.times.5
cm, about 3 cm.times.4 cm, about 3 cm.times.5 cm, about 5
cm.times.5 cm, about 4 cm.times.5 cm, about 5 cm.times.7 cm, about
1.5 cm.times.3.5 cm, about 7.5 cm.times.15 cm, about 9.5
cm.times.15 cm, about 7.5 cm.times.17 cm, and other sizes and
ranges there between.
In a variety of embodiments of the present technology, the base
and/or cover are each individually made of a singular piece of
plastic, preferably a biocompatible plastic. Alternatively, in
other embodiments, the base and the cover can be made collectively
from a singular piece of plastic, again preferably a biocompatible
plastic. For example, in such embodiments, the singular piece of
plastic can be folded such that the base and the cover are formed
and interact with one another, preferably temporarily. Further, the
first side of the base can be continuous with a first side of the
cover. Thus, a membrane, tissue, graft, or other biological
material may be placed between the first side of the base and the
first side of the cover, wherein a second side of the cover is
facing externally to the membrane. In still further embodiments,
the base and the cover may each be or collectively be a single
piece of biocompatible plastic produced by 3-D printing. In other
embodiments, the single piece of plastic for each of the base and
cover may have latches, handles, or other forms of attachment and
connection that can connect the base to the cover and vice versa.
For the example, the first side of the base can be fixedly attached
or connected to the first side of the cover via two interlocking or
connecting handles or a hook and latch enclosure system, for
example.
In further embodiments, the base and the cover can be made of, for
example, at least two substrates. In some embodiments, the
substrates are two of the same or different biocompatible plastics.
In other embodiments, the base and the cover are comprised of the
same type of substrate while in other embodiments the cover and
base are made from different substrates. Thus, one of ordinary
skill in the art will appreciate that a variety of substrates can
be utilized to make the various parts of the presently described
technology as long as the sufficient characteristics of the
components allow for the support, stabilization, temporary
connection or attachment of the selected membrane thereto with a
sufficient surface traction to prevent injury, damage, detachment
of the membrane during manufacturing, storage, transporting,
handling and end application or usage. To illustrate, in still
further embodiments, the base and the cover are made from different
types of substrates, with the different types of substrates being
different types of biocompatible plastics, biopolymers,
biocopolymers, or other biocompatible materials. More particularly
different types of biocompatible plastics, for example, may be a
single plastic composition, a multiple-composition plastic, or
layers of a biocompatible plastic(s) selected. As should be
appreciated by those skilled in the art, further alternatives are
also envisaged.
Communication Between the Base and the Cover
In some embodiments of the present technology, and with reference
to FIGS. 5A-7B, the device, article of manufacture, system and/or
composition comprises a base 30, a cover 60, and at least one
location (attachment point 22, 24) in which the base and the cover
are in operative communication, which can be direct communication
(e.g., temporary direct communication) or indirect communication
(e.g., temporary indirect communication) through a membrane 20 as
disclosed herein. In other embodiments, the base 30 and cover 60
are in sufficiently close proximity and are attached to one another
and/or to a membrane 20 by temporary or removable attachments or
connections. Suitable methods of communication can include, but are
not limited to, heat sealing, cauterization, welding, ultrasonic
welding, a biocompatible adhesive (preferably an adhesive suitable
for use with biological and/or cellular materials), use of a laser,
use of an interconnecting means, crimping (by heat or mechanically
by pressure), crunching, stapling, or clamping, among others.
Preferably, the attachment or connections include, but are not
limited to, at least one discrete cauterization point, at least one
latch, or at least one ultrasonic welding point by which the cover,
membrane (tissue, graft, or other biological material(s)) and base
are temporarily connected or attached. To illustrate, a sufficient
number of cauterization points (attachment points 24) can be
utilized to attach the membrane 20 (tissue, graft, or other
biological material(s)) to the cover 60 and a sufficient number of
cauterization points (attachment points 22) can be utilized to
attach the membrane 20 (tissue, graft, or other biological
material(s)) to the base 30 as well. Optionally, when the membrane
20 has a smaller length and/or width than the cover 60 and the
membrane receiving portion 40 of the base 30, a sufficient number
of cauterization points (or other attachment points) can be
utilized to attach the cover directly to the membrane receiving
portion, with the membrane being inwardly spaced from such
attachment points. Thus, it is contemplated that the membrane 20
can be secured between the cover 60 and the base 30 without
directly attaching the cover and/or the base to the membrane at an
attachment point. It should be appreciated by those skilled in the
art that any number of cauterization points or other temporary
attachments between the membrane (tissue, graft, or other
biological material(s)) and the cover and/or base can be used in
the practice of the present technology. Further, the level of
temporary attachment can be varied depending upon the type of
material used to make the cover and/or base as well as the type,
size, depth (among other variables) of the membrane, tissue, graft
or other biological material(s) temporarily attached, connected, or
applied thereto (i.e., temporarily attached or connected to the
cover, the base or both). In exemplary aspects, the attachment
points (e.g., cauterization points) can be generally positioned in
the outer edge portions of the cover 60, base 30, and membrane 20,
thereby minimizing functional damage to these components.
Focusing upon the connective relationship between the cover and
base, in some additional embodiments, the at least one connection
or attachment location in which the base and the cover are in
communication with one another (inclusive or not inclusive of the
membrane, tissue, graft, or other biological material(s)) comprises
one or more interconnecting means or connective devices, connectors
and the like. For example, the communication can be a female
connector and a male connector, wherein the male connector secures
into the female connector to provide a suitable attachment between
the base and the cover. The suitable connection may be disrupted by
sufficient force to remove the male connector from the female
connector. In other embodiments, the female connector can comprise
an indentation while the male connector can comprise a protrusion
in a shape suitable to fit or connect within the indentation.
Again, these examples are for illustrative purposes only and are
not an exhaustive exemplary listing.
It should also be appreciated that the number of temporary
connection or attachment locations or points between the base and
the cover, as well as the base and/or cover and the membrane
(tissue, graft, or other biological material(s)) depends on the
manufacturing processes and handling processes utilized as well as
the type of membrane (tissue, graft, or other biological
material(s)) selected. However, in accordance with the practice of
the present technology, the number of temporary connection or
attachment locations must provide sufficient traction, adhesion,
attachment or connection to withstand multiple stresses experienced
during processing, storage, transport, handling and
usage/application. For example, the number of connection or
attachment locations must be sufficient to ensure the associated
membrane, tissue, graft, or other biological material(s) remains
temporarily attached, adhered, or connected to the cover and/or
base while enduring fluid shear force created during manufacturing
of the present technology or its packaging, during cryopreservation
and thawing and also during transit should the cryomedium
potentially thaw prematurely, shift, move or otherwise develop
shear forces and the like that could potentially affect the
membrane interacting therewith.
Additionally, as further described herein, the number of connection
or attachment locations of the present technology (i.e., those of
the cover and the base as well as those of the cover and/or base to
the membrane, tissue, graft, or other biological material(s)) must
be able to withstand storage (including, for example,
cryopreservation (as well as the step of the inclusion or addition
of a cryopreservation medium provided during the manufacturing or
storage process)). Moreover, the connection or attachment locations
also are preferably capable of withstanding temperature changes,
including temperature changes ranging from 60.degree. C. to
-196.degree. C. (.+-.5.degree. C.), alternatively from about
80.degree. C. to about -196.degree. C..+-.5.degree. C.
(alternatively from about 40.degree. C. to about -196.degree. C.
(.+-.5.degree. C.) for a membrane or biological material containing
viable cells), among others. Conversely, the connection or
attachment locations and/or points of the present technology are
also preferably capable of withstanding the temperature variances
and other forces associated with thawing of the device,
composition, article of manufacture, or system of the present
technology. For example, such connection or attachment locations
preferably are maintained when the device, composition, article of
manufacture, or system is unthawed from about -80.degree. C. or
-196.degree. C. (.+-.5.degree. C.) to about room temperature.
(20.degree. C. to about 25.degree. C.) or about 40.degree. C.
(.+-.5.degree. C.). Further, the connection or attachment locations
and/or points of the present technology described herein also
preferably are capable of withstanding additional handling prior to
final application or usage such as during washing of the device,
composition, article of manufacture, or system during the
performance of a thawing procedure.
The number of connection or attachment locations will depend upon
the connection or attachment properties of the membrane, tissue,
graft or other biological material(s) utilized and the type of
material (e.g., a plastic substrate selected) used to form the
cover and/or the base. The number of connection or attachment
locations should allow for easy removal of the cover without
disturbing the further attachment or connection between the
membrane, tissue, graft, or other biological material(s) and the
base. Further, the connection(s) or attachment(s) between the base
and the membrane (tissue, graft, or other biological material(s))
should also be easily broken without tearing or damaging the
membrane (tissue, graft, or other biological material(s)).
Additionally, the connection(s) or attachment(s) between the base
and/or the top and the membrane should be such that they do not
contaminate, break-off, or pollute the membrane. Moreover, the
connection(s) or attachment(s) between the base and the membrane
(tissue, graft, or other biological material(s)) should allow a
handler (e.g., a health care provider) to easily remove and apply
the membrane, tissue, graft or other biological material(s) to an
end user (e.g., a patient having a wound or tissue defect) or for
use in an end use application.
In further embodiments of the present technology, the connection or
attachment locations can be a latch or latch system. A latch may be
any mechanical fastener that is used to join two or more objects or
surfaces together while allowing for the regular separation of the
objects or surfaces so connected or attached. A latch may consist
of a fastener that engages a catch, groove, hole, or suitable
equivalent to temporarily affix or hold the base and the cover in
close proximity. Suitable latching systems are known in the art.
The latch may also consist of at least one flexible singular piece
of substrate (e.g., a biocompatible plastic) that engages with a
hole (or alternatively over the edge of) the base and/or cover to
retain each so that they are in close proximity, preferably in a
temporary fashion or manner. Finally, the at least one connection
or attachment location for coupled communication between the base
and the cover may also include discrete points or regions. In other
embodiments, the at least one attachment or connection location may
be at least one side or a portion of a side of the base and cover.
In some embodiments, the coupled communication may be at least two
sides (or portions of each side), alternatively at least three
sides (or more) (or portions of such sides), among others.
Substrate Selection
In some aspects, the base 30 and/or the cover 60 can comprise any
compatible substrate for the practice of the present technology,
preferably a biocompatible substrate. The substrate can provide
structural integrity or support to the membrane 20 for handling
during any of the phases described herein (e.g., manufacture,
storage, transport and/or final application). In some instances,
the substrate may be a suitable composition that is not chemically
or physically altered by cryopreservation solutions (for example,
solutions containing Dimethyl Sulfoxide (DMSO). In some aspects,
the substrate is also not chemically or physically altered by
abrupt or large changes in temperature, and can be used within a
wide temperature range (e.g., -196.degree. C. to 60.degree.
C..+-.5.degree. C.). In other embodiments, the substrates are made
of polymers, copolymers, or biocompatible materials (e.g.,
plastics) that are thermal compatible and compatible with use with
cryopreservation solutions. Suitable plastics include, but are not
limited to, low density polyethylene (LDPE), high density
polyethylene (HDPE), ECTFE or ETFE copolymer (Ethylene
ChloroTriFluoroEthylene or Ethylene tetrafluoroethylene) FEP
(fluorinated ethylene propylene), PE (Polyethylene) PP
(Polypropylene), PMP (Polymethylpentene), Teflon.RTM., PS
(Polystyrene), RESMER.TM. (also known as RESMER Manufacturing
Technology commercially available from Thomas Scientific of
Swedesboro, N.J.), EVA, among others. However, it should be
appreciated by those skilled in the art that in those embodiments
of the present technology in which a cryopreservation media is not
utilized, other suitable substrates are envisaged in the practice
of the present technology.
In further embodiments of the present technology, the base 30 of
the present technology may comprise a material suitable for use
with biological or cellular materials, for example, a bio- or
cellular-compatible plastic. In additional embodiments, the cover
60 may comprise a material suitable for use with biological or
cellular materials, for example, a bio- or cellular-compatible
plastic. The plastic may be a composite of different plastics or a
homogenous plastic composition. Further such plastics may be
combinations of plastics, layers of one or more types of plastics,
among other plastics combinations. Again, preferably, the plastics
utilized in the practice of the present technology are
biocompatible plastics that are further preferably, made of medical
grade quality. It is also preferable that the substrates used in
the practice of the present technology should be capable of
withstanding a wide range of temperature changes ranging from about
40.degree. C..+-.5.degree. C. to about -196.degree. C..+-.5.degree.
C., preferably from about 40.degree. C..+-.5.degree. C. to about
-80.degree. C..+-.5.degree. C. The substrates should be capable of
withstanding freezing temperature from about -80.degree.
C..+-.5.degree. C. to about -196.degree. C..+-.5.degree. C.
Substrates should also be capable of remaining at about room
temperature (about 20.degree. C. to about 25.degree.
C..+-.5.degree. C.), during refrigeration (about 4.degree. C. to
about 8.degree. C..+-.5.degree. C.), and during freezing (from
about -20.degree. C..+-.5.degree. C. to about -196.degree.
C..+-./-5.degree. C.), alternatively from about -45.degree. C. to
about -50.degree. C..+-.5.degree. C., alternatively from about
-80.degree. C. to about -196.degree. C..+-.5.degree. C. For
substrates used with cellular membranes, the substrates should be
capable of withstanding a wide range of temperatures from about
60.degree. C. to about -196.degree. C. (.+-.5.degree. C.). Suitable
biocompatible plastics may include, but are not limited to plastics
that withstand exposure to a cryopreservation solution and/or
membrane, tissue, graft or other biological material(s) without
chemical alteration of its composition and/or alternatively,
damaging, injuring, or otherwise harming the membrane (tissue,
graft, or other biological material(s)), including harming viable
cells associated therewith. Suitable biocompatible plastics can
also include, for example, plastics capable for use in 3-D printing
applications or manufacturing procedures.
Compositions, Devices, Articles of Manufacture and Systems
Some aspects of the present technology provide compositions,
devices, articles of manufacture and systems (e.g., a membrane
product package 100) comprising a base 30, a cover 60, and a
membrane 20 (tissue, graft or other biological material(s)
temporarily associated with each. Again, the base 30 preferably
comprises at least one membrane receiving portion 40 wherein the
membrane receiving portion temporarily contacts, supports and holds
at least one membrane 20 (tissue, graft, or other biological
material(s)). The membrane receiving portion 40 also preferably
provides sufficient surface traction to maintain the temporary
adherence, attachment or connection of the membrane 20 (tissue,
graft, or other biological material(s)) to the base 30 without
curling of the edges of that membrane (tissue, graft, or other
biological material(s)).
In other embodiments, and with reference to FIGS. 5A-7B, the
membrane 20 (tissue, graft, or other biological material(s)) is
temporarily attached via at least one attachment or connection
location associated with the base 30. However, it should be
appreciated by those skilled in the art that the membrane 20
(tissue, graft, or other biological material(s)) may be temporarily
attached, connected, or adhered to the base by more than one
location, preferably two or more, three or more and the like. The
locations, as described herein, may be discrete connection or
attachment points 22 between the membrane 20 (tissue, graft, or
other biological material(s)) and the base 30, including, but not
limited to, cauterization points, points attached via a
biocompatible adhesive, heat welding, cauterization, ultrasonic
welding, and other suitable attachment procedures for use with
biological or cellular materials. The number of locations 22 in
which the membrane 20 (tissue, graft, or other biological
material(s)) is temporarily attached to the base 30 is sufficient
to maintain, preferably, the planar orientation of the membrane
(tissue, graft, or other biological material(s)) without curling or
rolling of the edges thereof on the base, and further to provide a
sufficient adhesion, attachment or connection such that the
membrane (tissue, graft, or other biological materials(s))
preferably does not significantly move or slide during handling
(e.g., when attaching the cover, adding a cryopreservation medium,
during storage, during transport, or removing the cover prior to
end use application).
The temporary attachment or connection points 22 of the membrane 20
(tissue, graft, or other biological material(s)) to the base 30 may
also be in a pattern. For example, a suitable pattern for
temporarily attaching or connecting the membrane (tissue, graft, or
other biological material(s)) to the base can be at least one
connection or attachment point 22 in each corner of the base 30 (or
membrane receiving portion 40 thereof); at least one attachment
point 22 in a middle portion of the upper edge (e.g., the edge
farthest away from the handling portion, if applicable) of the base
30 (or membrane receiving portion 40 thereof), as viewed from the
top, looking down at the base 30; and at least one connection or
attachment point 22 in a middle portion of the lower edge of the
base 30 (or the lower edge of the membrane receiving portion 40
thereof), as viewed from the top, looking down at the base 30.
Other suitable patterns are also envisaged, including the exemplary
patterns displayed in Tables 7 and 8. Further, additional suitable
patterns can also include at least one attachment point in each
corner of the membrane receiving portion 40 of the base and at
least one attachment point in a middle portion of the lower edge of
the base. In some instances the at least one attachment point
comprises attachment points at the four corners of the membrane
receiving portion; in some instances, the attachment points are
additionally in middle portions of the edges defined between the
corners of the membrane receiving portion. In an exemplary
embodiment, the membrane can be attached to the base at least at
the four corners and at least at one point in a middle portion of
the upper and/or lower edge. The cover may be attached to the
membrane and/or the base by at least one attachment point,
preferably at least two attachment points, more preferably at least
at three attachment points. The at least one attachment point may
be a discrete point in a middle portion along one or more edges of
the membrane receiving portion and/or the cover. For example, the
three attachment points may be at two middle points along side
edges of the membrane receiving portion and/or the cover and at one
middle point along the upper edge of the membrane receiving
portion.
The Membrane
As provided herein, it should be appreciated that the present
technology can be utilized for membranes, tissues, grafts, and
other biological materials, collectively referred to herein as
"membranes" 20. Thus, the term "membrane" or "membranes" shall be
used expansively throughout the instant specification to encompass
various cellular and/or biological materials suitable for use in
the practice of the present technology. It should also be
appreciated by those skilled in the art that "membrane" or
"membranes" of the present technology can comprise natural
"membranes", synthetic "membranes" or combinations or derivatives
thereof. For example, natural membranes can include but are not
limited to grafts, naturally derived membranes, and bioengineered
membranes comprising living cells, further including, but not
limited to, placental membranes, skin grafts, in vitro cultured
grafts, tendon grafts, among others. Natural membrane may include
allografts, autografts or xenografts. Natural membranes may be
derived from mammals, including, for example humans. Bioengineered
membranes can include living cells, extracellular matrix,
biomolecules, at least one type of cytokine, and combinations or
derivatives thereof. Based on the structure of the bioengineered
membranes, other suitable materials or biomolecules may be
associated with the membrane. Other natural membrane may include,
for example, at least one natural fiber, for example, silks.
Further non-natural or synthetic membranes, for example, can
include but are not limited to membranes containing at least one
synthetic fiber or compound, such as nylon, copolymers, polymers,
including, but not limited to, PVA (polyvinyl acetate), PLA,
(polyactic acid), PGA (polyglycolic acid), PCL (polycaptolactone),
PLGA (poly(lactic-co-glycolic) acid), and the like. Further, it
should be appreciated that suitable membranes can also include
chorionic membrane products, amniotic membrane products,
combinations thereof and other placental membrane products.
Placental membranes products that can be used with the present
technology are disclosed in U.S. application Ser. No. 13/030,507
(Publication No. 2011/0212158); Ser. No. 14/069,894 (Publication
No. 2014/0140966); Ser. No. 14/070,035 (Publication No.
2014/0127317); Ser. No. 14/172,940 (Publication No. 2014/0294777);
Ser. No. 14/056,101 (filed Oct. 17, 2013); Ser. No. 14/070,040
(Publication No. 2014/0127177); Ser. No. 14/272,343 (Publication
No. 2015/0010609); and Ser. No. 14/291,256 (Publication No.
2014/0301986), in the name of Osiris Therapeutics, Inc. of
Baltimore, Md., all of which are incorporated by reference in their
entireties. Suitable amniotic membrane product includes Grafix.RTM.
Prime.RTM. (Osiris Therapeutics, Columbia, Md.). Suitable chorionic
membrane products include, for example, Grafix.RTM. Core.RTM.
(Osiris Therapeutics, Columbia, Md.).
Other suitable grafts for use in the practice of the present
technology can also include, for example, grafts containing viable
cells. Some suitable grafts, for example contain fibroblasts,
epithelial cells, stem cells, mesenchymal stem cells, and
compositions comprising various combinations thereof. In some
embodiments, the compositions comprising viable fibroblast and
epithelial cells.
Suitable bioengineered grafts include grafts in which viable cells,
for example fibroblasts, stem cells, epithelial cells, mesenchymal
stem cells, which are seeded onto a synthetic or natural membrane.
The cells are cultured to provide a sufficient membrane structure.
Based on the structure of the bioengineered membranes, other
suitable materials or biomolecules may be associated with the
membrane. For example, bioengineered grafts may contain
extracellular matrix, biomolecules including, but not limited to,
cytokines, growth factors, co-stimulatory molecules, proteoglycans,
and the like. In some instances, the bioengineered grafts may not
include viable cells, and may include other biological membrane
components, including, but not limited to, extracellular matrix
(e.g., collagen, proteoglycans), biomolecules and the like.
As can be illustrated by the present technology it was surprisingly
found that, the described compositions, devices, articles of
manufacture and/or systems (e.g., the disclosed support assembly
and membrane product package 100) maintain the viability of the
temporarily attached, connected, or adhered cells in the membranes.
Such an outcome is advantageous as the present technology provides
various packaging or packaging system embodiments that support,
protect, contain and maintain live cells (e.g., naturally derived
membranes or bioengineered membranes) for use in a variety of
therapeutic, diagnostic, experimental and/or analytical
applications/uses unlike the conventional packaging, packaging
systems and non-living cellular packaging products of the prior
art.
Further, the compositions, devices, and systems of the present
technology also were surprisingly found to maintain the viability,
reduce or prevent injury or damage and maintain an ease of removal
and application of the cells in the temporarily attached membranes
even during a variety of environmental stresses such as
manufacturing, processing, cryopreservation, freezing, storage,
thawing, transporting, and final application/use of such membranes
(or cells). Such outcomes are advantageous for the support,
stability and protection of cellular or biological products in a
packaging or packaging system not envisaged by the conventional
art.
Further, the compositions, devices, articles of manufacture and
systems of the present technology may also maintain the integrity
of the membrane during a variety of environmental stresses, such
as, manufacturing, processing, cryopreservation, freezing, storage,
thawing, transporting, and final application/use of such membranes
(or cells).
The membrane 20 is preferably placed on the base 30 in an operative
position, which maintains the directionality of the membrane (e.g.,
epithelial cells or tissues on the cover and connective tissue
cells or tissue on the base). As described, the base and/or the
cover may be labeled to maintain the directionality with a marker
or label. Maintaining directionality is important in cellular
repair, especially when membranes which mimic the composition of
the skin are used. For example, some membranes may have a first
side (e.g., lower surface 28) and a second side (e.g., upper
surface 26), where the first and second sides have different
compositions. For example, amniotic membranes derived from
placental tissue have a first side (e.g., lower surface 28)
containing stromal cells and a second side (e.g., upper surface 26)
containing epithelial cells. For application as a wound or tissue
defect repair composition, it is important to maintain the
directionality of the membrane. The first side containing stromal
cells should make direct contact with the tissue defect or wound,
and the epithelial layer should face exterior to the wound,
mimicking the structure of the epidermis.
Membranes utilized in the practice of the present technology may be
any suitable size and customizable depending on the type of
membrane and the particular end application or usage of that
membrane. Suitable sizes (length.times.width) of membrane include,
but are not limited to, about 1.5 cm.times.about 1.5 cm, about 2
cm.times.about 2 cm, about 3 cm.times.about 3 cm, about 4
cm.times.about 4 cm, about 5 cm.times.about 5 cm, about 6
cm.times.about 6 cm, about 7 cm.times.about 7 cm, about 8
cm.times.about 8 cm, about 7.5 cm.times.about 15 cm, about 1.5
cm.times.about 2 cm, about 1.5 cm.times.about 3 cm, about 2
cm.times.about 3 cm, about 3 cm.times.about 4 cm, about 2
cm.times.about 5 cm, about 3 cm.times.about 5 cm, about 4
cm.times.about 5 cm, about 5 cm.times.about 7 cm, about 5
cm.times.about 10 cm, about 5 cm.times.about 15 cm, and include any
variations or sizes and ranges there between, in increment of 0.1
cm to 1 cm.
The compositions (e.g., kits) may further comprise a container. The
container may be used to store the membrane-containing device or
composition (e.g., the membrane product package 100). Additionally,
the container may be used for cryopreservation, for handling and
shipping of the membrane. The container allows for the addition of
cryopreservation solution to the membrane. The container may be a
bag or receptacle, or other suitable container. The container is
made from a material which is able to be sterilized, can withstand
cryopreservation solution and also a wide range of temperatures
and/or freeze/thaw cycles without becoming brittle or loosing
integrity. Suitable containers include plastic cryopreservation
bags, including, for example OSRSFP-90 Cryogenic Storage bag.
In some embodiments, the composition (e.g., kit) further comprises
cryopreservation solution. The cryopreservation solution is added
to the container containing the membrane-mounted device or
composition. Preferably, a sufficient amount of cryopreservation
solution is added to the container to protect the membrane during
the subsequent freezing steps. The base containing the membrane
receiving portion allows for sufficient infusion of the membrane
with the cryopreservation solution to maintain viability of the
cells contained within the membrane. Suitable cryopreservation
solutions are known in the art. In one embodiment, the
cryopreservation comprises storage in a cryopreservation medium
comprising one or more cell-permeating cryopreservatives, one or
more non-cell permeating cryopreservatives, or a combination
thereof. Suitable cryopreservatives include, but are not limited
to, DMSO, a glycerol, a glycol, a propylene glycol, an ethylene
glycol, propanediol, polyethylene glycol (PEG), 1,2-propanediol
(PROH) or a combination thereof. In some embodiments, the
cryopreservation solution may contain one or more non-cell
permeating cryopreservative selected from polyvinyl pyrrolidione, a
hydroxyethyl starch, a polysaccharide, a monosaccharide, an
alginate, trehalose, raffinose, dextran, human serum albumin,
ficoll, lipoproteins, polyvinyl pyrrolidone, hydroxyethyl strarch,
autologous plasma or a combination thereof. Other examples of
useful cryopreservatives are described in Cryopreservation
(BioFiles, Volume 5, Number 4 Sigma-Aldrich.RTM. Datasheet).
For example, a suitable cryopreservation solution comprises a
cryopreservative, in an amount of at least about 0.001% to 100%,
suitably in an amount from about 2% to about 20%, preferably about
5% to about 10% by volume. In some instances, the cryopreservation
solution comprises at least about 2% cryopreservative. Further, the
cryopreservation solution may comprise serum albumin or other
suitable proteins. In some embodiments, the cryopreservation
solution comprises from about 1% to about 20% serum albumin or
other suitable proteins, alternatively from about 1% to about 10%.
Serum albumin or other suitable proteins are present to help
stabilize the membrane during the freeze-thaw process and to reduce
the damage to cells, maintaining viability. Serum albumin may be
human serum albumin or bovine serum albumin. The cryopreservation
solution may further comprise a physiological buffer or saline, for
example, phosphate buffer saline.
The container is filled with sufficient amount of the
cryopreservation solution to cover both sides of the membrane. The
amount of the cryopreservation solution necessary will depend on
the type of container used and the size of the container relative
to the size of the membrane-containing composition or device (e.g.,
membrane product package 100). The lower the amount of
cryopreservation solution necessary to cover the
composition/device, the faster the composition is able to thaw.
Thus, it is desirable to use the least amount of cryopreservation
solution that allows for top coverage of the membrane without
compromising viability of the cells during the freeze thaw.
Further, the smaller the membrane and the smaller the container
used, the less cryopreservation solution can be used.
In some embodiments, a bag is used containing cryopreservation
solution in an amount from about 7 ml to about 50 ml, alternatively
from about 10 ml to about 50 ml, alternatively from about 15 ml to
about 50 ml, alternatively from about 15 ml to about 25 ml. In one
preferred embodiment, about 15 ml of cryopreservation solution is
added to the container or bag. The amount of cryopreservation
solution can be sufficient to fully submerge the membrane. The
amount will depend on the size of the bag used and the size of the
membrane being cryopreserved. If a small bag is being used with a
small (e.g. smaller than 2 cm.times.2 cm membrane), about 3 ml to
about 10 ml, alternatively 3 ml to about 7 ml of cryopreservation
solution may be used.
In some embodiments a container is used containing from about 7 ml
to about 50 ml, alternatively from about 5 ml to about 20 ml,
alternatively from about 7 ml to about 20 ml, alternatively from
about 7 ml to about 15 ml. The amount of cryopreservation solution
can be sufficient to fully submerge the membrane within the
container. The amount will depend on the size of the container used
and the size of the membrane being cryopreserved.
In some embodiments, the amount of cryopreservation solution is
sufficient to protect cells during the freezing and subsequent
thawing procedures. In some embodiments, at least 70% cell
viability is maintained after a freeze-thaw. In some aspects, at
least 75% cell viability is maintained, alternatively about 80%
cell viability is maintained, alternatively 85% cell viability is
maintained, alternatively about 90% cell viability is maintained,
alternatively about 95% cell viability is maintained. In some
embodiments, at viability of the membrane is at least 70%, at least
71%, at least 72%, at least 73%, at least 74%, at least 75%, at
least 75%, at least 78%, at least 80%, at least 82%, at least 85%,
at least 88%, at least 89%, at least 90%, at least 92%, and
percentages in between.
In some embodiments, the amount of cryopreservation solution is
sufficient to protect the structural, architectural, and or 3-D
structure of the membrane, including acellular matrixes. In some
embodiments, the cryopreservation solution contains a
cryopreservative in an amount of 0.01% to about 100%, alternatively
from about 2% to about 100%. In some embodiments, the
cryopreservation solution contains polysaccharides or
monosaccharides.
Methods of Using, Employing, or Applying the Compositions, Devices,
Articles of Manufacture, or Systems
In various embodiments of the present technology, a method of
making a cryopreserved packaging product, cryopreserved cellular
packaging product, or cryopreserved therapeutic packaged product
(e.g., a membrane product package 100) is provided, among others.
The methods comprise, for example, the steps of providing at least
one membrane to be cryopreserved; adhering, connecting or
attaching, preferably temporarily, the membrane to at least one
membrane receiving portion of a base; adhering at least one cover
to the membrane and base; placing the then membrane-containing base
and cover into a storage receptacle; filling the storage receptacle
with a sufficient amount of at least one cryopreservation media
(e.g., a cryopreservation solution) to submerge, immerse, or
permeate (partially or completely) the membrane containing base and
cover combination; placing the storage receptacle within a
refrigerated environment at about 2.degree. C. to about 8.degree.
C. for at least about 10 minutes, preferably about 30 to about 60
minutes; and then subsequently subjecting the membrane containing
base and cover combination to a freezing environment, thus freezing
the container to preferably about -80.degree. C. The cryopreserved
product (i.e., the membrane containing base and cover combination
of the present technology) should remain frozen until thawed for
use. In other embodiments, the method of adhering, connecting or
attaching the membrane to the base comprises cauterizing the
membrane to the base at least at one point, alternatively at least
at three points, alternatively at least at five points,
alternatively at least at six points. Further, the method of
adhering the membrane to the base could comprise using a
biocompatible adhesive to adhere at least one point between the
membrane and the base, preferably at least five points,
alternatively at least six points. In other embodiments, the cover
is adhered, connected or attached to the membrane-containing base
by cauterizing at least at one point, alternatively at least at
three points. Further, the adhering can be done by using an
adhesive at least at one point between the cover and the
membrane-containing base, at least at two points, at least at three
points.
In some methodology embodiments of the present technology, a method
of cryopreserving a membrane is provided comprising the steps of:
a) preparing a membrane; b) adhering the membrane to the device (or
composition, article of manufacture, or system of the present
technology) as described herein; c) placing the device comprising
the membrane in a sterile receptacle; d) applying a
cryopreservation media (e.g., a cryopreservation solution) to the
device in the receptacle, wherein the device comprising the
membrane is partially or completely submersed, immersed, or is
permeated in the cryopreservation media, and e) cryopreserving the
sterile holder and device (i.e., containing the selected membrane)
at a temperature of about -80.degree. C. In other embodiments, the
method of cryopreserving a membrane may comprise the steps of:
preparing a composition (or device, article of manufacture, or
system of the present technology) as described herein; placing the
composition in a sterile receptacle; applying a cryopreservation
media (again, e.g., a cryopreservation solution) to the device in
the receptacle, wherein the device (i.e., further comprising the
membrane) is submerged, immersed, permeated partially or fully in
the cryopreservation media; and cryopreserving the sterile
receptacle and device at a temperature of about -80.degree.
C..+-.5.degree. C. to about -196.degree. C..+-.5.degree. C.
Kits
Packaging kits comprising the compositions, devices, articles of
manufacture, devices and systems of the present technology are also
provided. The kits can comprise, for example, a device comprising a
base containing a membrane receiving portion and a cover with or
without the temporarily attached membrane as described herein. The
kits can further comprise a device (composition, article of
manufacture, or system) of the present technology and instructions
for adhering, attaching or connecting, preferably temporarily, the
membrane as described herein to, preferably between, the base and
the cover in some manner or fashion that meets the goals and
advantageous of the present technology as described herein. In
other aspects, the kits can provide further instructions on
maintaining the directionality of the membrane when applied,
attached, adhered or connected to the cover and/or base as well
when stored, transported, handled and finally applied to a wound or
tissue defect, or when used in another application. For example,
such instructions can provide placing a first side of the membrane
facing the base and a second side facing the cover. Thus, the
directionality of the membrane can be maintained, for example,
during storage and application. The kit may further comprise at
least one adhesive, such as at least one bio-adhesive. Thus, in
some aspects, the kits of the present technology provide
instructions for preferably temporarily adhering, attaching, or
connecting the membrane to the base at least at one point,
alternatively adhering, connecting, or attaching (preferably
temporarily) the membrane at least at three points to the base,
alternatively adhering, connecting or attaching (preferably
temporarily) the membrane at least at five points to the base,
alternatively adhering, attaching or connecting (preferably
temporarily) the membrane at least at six points to the base. In
other respective aspects, the instructions of the present
technology can provide instructions as to how to cauterize the
membrane at varying points to the base. In other aspects, the
instructions of the present technology can provide a method of
using a bio-adhesive to adhere, attach, or connect (again,
preferably temporarily) the membrane to the base at specific points
by applying the bio-sealer to at least one point between the
membrane and base. In some aspects, the kit comprises instructions
on adhering, connecting or attaching the cover to the base, wherein
the membrane is located between the cover and the base. In some
embodiments, the cover is adhered, connected or attached to the
membrane at least at one point, preferably at least at three
points. In such embodiments, the adherence may be to the membrane
itself or pass through the membrane to the base. The points of
attachment may be discrete points along the edge, over the partial
or whole length of one or edges, or over the entire surface
area.
Kits of the present technology for treating a tissue defect are
also provided herein. The kits may comprise a composition (or
device, or article of manufacture, or system) comprising at least
one membrane, a base and at least one cover as described herein.
The kit may also provide for a cryopreserved membrane as described
herein. The kit can also comprise at least one set of instructions
for thawing the membrane. The kit may further comprise
instructions, for example, for rinsing or washing the membrane
(e.g., once thawed if previously cryopreserved) and instructions
for applying (e.g., in an oriented manner or position) the membrane
to at least one wound or at least one tissue defect of a patient
(human or animal). Such kits of the present technology may also
include at least one preparation guide for preparing a tissue
suitable for use in accordance with the practice of the present
technology. Such kits may include, for example, an application
guide as to how to apply the membrane to a wound or tissue defect.
Alternatively, the application guide may comprise, for example,
instructions on how to remove the cover from the membrane-bound
base and methods of how to slide the membrane from the base onto a
suitable treatment site or for other use. Further, such kits may
contain a sizing chart and instructions for sizing the membrane to
a preferable size depending on the application or treatment site
size. Such an outcome of the present technology allows for a health
care provider to customize or tailor the membrane selected prior to
or during the resultant procedure with the patient. Such real time
or on-demand capability has been surprisingly found by use of the
present technology and overcome several limitations of the prior
art in which fixed membrane products and product sizes do not allow
for such customization, much less on a real time or on-demand
basis.
In still further embodiments, the kits of the present technology
further comprise a cutting device, for example scissors or a
scalpel. In other embodiments, the kit may contain a buffer or
thawing medium as well as other media necessary for the particular
use or application of the membrane contained therein. In other
embodiments, the kits of the present technology may contain, for
example, forceps, tweezers, and other handling media. In some
embodiments, the kit further comprises a container.
Methods Concerning the Compositions, Devices, Articles of
Manufacture and Systems of the Present Invention
The methods, compositions, devices, articles of manufacture and
systems of the present technology described herein provide for a
"membrane" as set forth herein which maintains or provides at least
about 70% viable cells for application to an end user (e.g., to a
wound or a tissue defect) or for other diagnostic, experimental, or
analytical uses. It has been surprisingly found that the methods,
compositions, devices, articles of manufacture and systems of the
present technology allow for the support and protection of living
or fresh cellular materials for later use post-manufacture,
storage, preservation, transport and handling prior to final
application or use unlike that of the prior art. Moreover,
significant therapeutic advantages can be achieved by the methods,
compositions, articles of manufacture, devices and systems of the
present technology due to the significantly enhanced and maintained
cellular viability. Further, costs are reduced, and treatment
modalities are streamlined or enhanced, all while providing a
convenient and ease to use approach for a handler of the presently
described packaging and/or packaging products.
Methods of applying a membrane to a patient (human or animal) in
need thereof are provided with respect to the present technology.
At least one method comprises the steps of (i) obtaining a device,
composition of matter, article of manufacture, or system of the
present technology described herein containing a membrane or
biological composition described herein which has been
cryopreserved and stored at about -80.degree. C. to about
-196.degree. C. The method can further comprise the steps of (ii)
thawing the membrane; (iii) optionally, rinsing or washing the
membrane with a sterile physiological solution or other suitable
biological medium; (iv) removing the cover from the membrane and
base; (v) and applying the membrane from the base onto the patient
as a unitary outcome or step. Optionally, the method can also
comprise the steps of (i) assessing the orientation of the membrane
as to the cover and the base to retain the orientation (or
directionality) of the membrane prior to application; and (ii)
applying the membrane with the proper orientation as provided by
the composition, device, articles of manufacture, or system of the
present technology. It should be appreciated by those skilled in
the art and as further described herein that the orientation can be
provided in a variety of manners including an optional directional
marker or label separate from or inclusive of the cover, the base,
or both the cover and the base.
In other embodiments, a method of applying a membrane to a patient
(human or animal) in need thereof comprises the steps of: 1)
thawing a receptacle (e.g., a bag, or other suitable receptacle for
biological or cellular materials) containing the cryopreserved
product of the present technology to about room temperature; 2)
removing the cryopreserved product from the receptacle; 3) rinsing
or washing the cryopreserved product in a physiological buffer,
physiological medium, or other suitable biological or cellular
medium; 4) removing the cover from the base and membrane; and 5)
sliding the membrane from the base in a singular step and applying
the membrane onto the area to be treated on the patient. The step
of sliding the membrane from the base may include the further steps
of breaking the temporary adherence, connection or attachment
between the membrane and the base at the at least one connection or
attachment location.
It has been surprisingly found that the compositions, devices,
articles of manufacture, systems and methods of the present
technology provide for the membrane to be slid from the base in a
manner which allows the handler (e.g., a health care provider) to
maintain the directionality of the membrane when applied to the
affected area or location without causing the membrane to curl,
fold over onto itself, or otherwise be significantly injured or
damaged during the application process. Such an ability, provides
for additional therapeutic outcomes of the present technology in
that a greater portion of the treatment area receives the membrane;
a greater amount of the viable cellular material of the membrane is
applied to the treatment area; potentially fewer applications of
the membrane need to be utilized to the patient (thus leading to
potentially improved treatment times); increased patient
compliance; increased health care provider receptivity to the use
of such cellular products, reduced cost, and other advantageous
outcomes. Further, because more of the end product of the present
technology can be preserved and applied, less waste occurs than
conventional products of a potential similar nature.
Moreover, because the end products of the present technology are
supplied in such a manner as described herein, the end user has the
ability to tailor the size and shape of the end product such that
the resultant membrane to be applied to a particular affected area
(or other application) can be done in a customized manner and
potentially in a real time, on demand manner as needed. This is
significantly different and improved over other conventional
products of a similar nature currently available.
Finally, the end products and method of application of the present
technology also surprisingly allow and provide for increased
handling comfort and increased safety within the medical discipline
because the end product edges can be smoothed. In doing so, the end
product of the present technology is easier to handle and does not
puncture or cut the handlers appendages. This is significant in the
health care industry where blood borne disease transmission is to
be prevented.
Further, the present technology surprisingly allows for a reduced
thaw time. As demonstrated in the examples herein, the thaw time
for cryopreserved membranes in the devices, compositions, articles
of manufacture or systems of the present technology is 10 fold
reduced as compared to conventionally packaged membranes. This
reduction in thaw time not only limits the time that the membrane
is exposed to cryopreservative factors, but also provides much for
convenience for the end user/health care provider that is applying
the membrane to a subject. As demonstrated, that thaw time for
packaged membrane of the present technology is about 3 to 4
minutes, as opposed to at least 30 minutes for a conventionally
packaged membrane. Also, in some instances, the reduction of time
exposed to thawed cryopreservation solution also can lead to
increased viability of the cells contained within the membrane.
It should also be appreciated by those skilled in the art that the
"membranes" of the presently described technology utilized in the
further methods of the present technology can be used for
application to a number of different types of wounds or tissue
defects. Tissue defects can include, but not limited to, wounds,
abrasions, lacerations, incisions, ulcers, corneal wounds, among
others. Ulcers include, but are not limited to, dermal ulcers.
Optionally, the wound is a laceration, scrape, thermal or chemical
burn, puncture, or wound caused by a projectile. Optionally, the
wound is an epidermal wound, skin wound, chronic wound, acute
wound, external wound, internal wounds, or congenital wound. Such
wounds may be accidental or deliberate, e.g., wounds caused during
or as an adjunct to a surgical procedure. Optionally, the wound may
be closed surgically prior to administration.
The membranes disclosed herein are also useful in treating a number
of wounds including: tendon repair, cartilage repair (e.g. femoral
condyle, tibial plateau), ACL (anterior crucial ligament)
replacement at the tunnel/bone interface, dental tissue
augmentation, fistulas (e.g., Crohn's disease, jejunal-tube-based,
tracheoesophogeal), missing tissue at adhesion barriers (e.g. nasal
septum repair, vaginal wall repair, abdominal wall repair, tumor
resection), dermal wounds (e.g. partial thickness burns, toxic
epidermal necrolysis, epidermolysis bullosa, pyoderma gangrenosum,
ulcers e.g. diabetic ulcers (e.g. foot), venous leg ulcers),
surgical wounds, hernia repair, tendon repair, bladder repair,
periosteum replacement, keloids, organ lacerations, epithelial
defects, and repair or replacement of a tympanic membrane.
For the variety of methods of application of the membrane via the
present technology, it is preferable that the application be via
topical administration. Alternatively, it can be used during
surgical applications.
In another embodiment, a membrane is administered to a subject to
topically treat a burn. Optionally, the burn is a first-degree
burn, second-degree burn (partial thickness burns), third degree
burn (full thickness burns), infection of burn wound, infection of
excised and unexcised burn wound, loss of epithelium from a
previously grafted or healed burn, or burn wound impetigo.
In a still further embodiment, a membrane is topically administered
by placing the membrane directly over the skin of the subject,
e.g., on the stratum corneum, on the site of the wound, so that the
wound is covered, for example, using an adhesive tape.
It should be appreciated by those skilled in the art that other
forms of administering or applying the present technology are also
envisaged. For example, the membrane delivered by the device,
composition, article of manufacture or system of the present
technology may be administered as an implant, e.g., as a
subcutaneous implant.
In yet further embodiment, a membrane is topically, cutaneously,
subcutaneously, and the like administered to the epidermis to
reduce features of aging skin or scarring. Such treatment is also
usefully combined with so-called cosmetic surgery (e.g.
rhinoplasty, rhytidectomy, etc.).
In another embodiment, a membrane is topically administered to the
epidermis to accelerate healing associated with a dermal ablation
procedure or a dermal abrasion procedure (e.g. including laser
ablation, thermal ablation, electric ablation, deep dermal
ablation, sub-dermal ablation, fractional ablation, and microdermal
abrasion).
Other pathologies that may be treated with present technology
include, for example, traumatic wounds (e.g. civilian and military
wounds), surgical scars and wounds, spinal fusions, spinal cord
injury, avascular necrosis, reconstructive surgeries, ablations,
and ischemia.
A membrane prepared and applied according to the present technology
can optionally be used to reduce adhesion or fibrosis of a wound.
Postoperative fibrosis is a natural consequence of all
surgically-based wound healing. By example, postoperative peridural
adhesion results in tethering, traction, and compression of the
thecal sac and nerve roots, which cause a recurrence of
hyperesthesia that typically manifests a few months after
laminectomy surgery. Repeated surgery for removal of scar tissue is
associated with poor outcome and increased risk of injury because
of the difficulty of identifying neural structures that are
surrounded by scar tissue. Therefore, experimental and clinical
studies have primarily focused on preventing the adhesion of scar
tissue to the dura matter and nerve roots. Spinal adhesions have
been implicated as a major contributing factor in failure of spine
surgery. Fibrotic scar tissue can cause compression and tethering
of nerve roots, which can be associated with recurrent pain and
physical impairment.
In additional aspects and embodiments of the present technology,
methods of maintaining the directionality of a membrane during
processing, storage, cryopreservation, or during application to a
subject (human or animal) are disclosed. The methods may comprise,
for example, the steps of preparing a membrane, wherein the
membrane has a first a second side, wherein the first and second
side comprise different compositions; and adhering the membrane to
the device (composition, article of manufacture or system also of
the present technology) disclosed herein, where the membrane is
disposed partially or completely between the base and cover. The
method can also comprise the step of adhering, attaching or
connecting the membrane to the cover and the base wherein the first
side of the membrane is facing and connects or attaches to the base
and the second side of the membrane is facing and connects or
attaches to the cover. Such a method may further comprise the step
of labeling the base and/or cover by a marker (e.g., a symbol) to
indicate the orientation or directionality of application of the
product, or alternatively the directionality of the membrane to be
applied or utilized in a manner where orientation is desired. In
some instances, the base is marked for orientation and the membrane
is attached via a predetermined orientation to the base.
In other embodiments, the methods of the present technology further
comprise the step of determining the adherence or surface traction
of the first side and the second side of the membrane to, for
example, the cover and/or the base, and orientating the membrane
such that the side of the membrane with higher surface traction is
facing the base. In some embodiments, the membrane comprises a
first side comprising stromal cells and a second side comprising
endothelial cells, wherein the first side is orientated to face the
base. In other embodiments, the first side of the membrane has a
greater adherence to the cover.
In the preceding paragraphs, use of the singular may include the
plural except where specifically indicated. As used herein, the
words "a," "an," and "the" mean "one or more," unless otherwise
specified. In addition, where aspects of the present technology are
described with reference to lists of alternatives, the technology
includes any individual member or subgroup of the list of
alternatives and any combinations of one or more thereof. Moreover,
the disclosures of all patents and publications, including
published patent applications, are hereby incorporated by reference
in their entireties to the same extent as if each patent and
publication were specifically and individually incorporated by
reference.
It is to be understood that the scope of the present technology is
not to be limited to the specific embodiments described above. The
present technology may be practiced other than as particularly
described and still be within the scope of the accompanying claims.
Likewise, the following examples are presented in order to more
fully illustrate the present technology. They should in no way be
construed, however, as limiting the broad scope of the technology
disclosed herein.
The presently described technology and its advantages will be
better understood by reference to the following examples. These
examples are provided to describe non-exhaustive embodiments of the
present technology. By providing these examples, the scope of the
presently described and claimed technology is not limited in spirit
or scope. It will be understood by those skilled in the art that
the full scope of the presently described technology encompasses at
least the subject matter defined by the claims appending this
specification, and any alterations, modifications, derivatives,
combinations, or equivalents of those claims. Further, the
citations provided herein are hereby incorporated by reference for
the cited subject matter.
EXAMPLES
Example 1: Producing a Composition, Device, Article of Manufacture,
or System According to the Present Technology
The following example demonstrates the use of a base and a cover of
the present technology with a membrane, e.g. a placental product.
The following procedure was used:
1. Placental membranes were prepared for placement in the packaging
or handling compositions, devices, articles of manufacture or
systems of the present technology. Methods of preparing placental
products, for example, are disclosed in U.S. patent application
Ser. No. 13/030,507 (Publication No. 2011/0212158); Ser. No.
14/069,894 (Publication No. 2014/0140966); Ser. No. 14/070,035
(Publication No. 2014/0127317); Ser. No. 14/172,940 (Publication
No. 2014/0294777); Ser. No. 14/056,101 (filed Oct. 17, 2013); Ser.
No. 14/070,040 (Publication No. 2014/0127177); Ser. No. 14/272,343
(Publication No. 2015/0010609); and Ser. No. 14/291,256
(Publication No. 2014/0301986), which are incorporated herein by
reference in their entireties.
2. In a pre-processing step, the membrane is prepared to size by
any suitable means. In this instance, the membrane was placed on
temporary nitrocellulose paper substrate to allow for convenient
handling and provides a template for cutting to size.
3. Tissue was removed from the nitrocellulose paper using forceps
and transferred onto the perforated plastic base. For amniotic
membrane, the stromal side is placed facing the perforations. The
tissue was adjusted to cover the entire area of the membrane
receiving portion of the plastic base. Any extra tissue was folded
over the base.
4. The tissue was cauterized at the points indicated in FIGS.
7A-7B. FIGS. 7A-7B depict a schematic representation of cautery
points on the plastic pieces (6 points on the base, left; 3 points
on the cover, right). Side portions of a cautery pen were used to
cauterize the four corners and the middle point of the cover. A tip
portion of a cautery pen was used to cauterize the base middle
point.
5. The cover was placed on top of the tissue and base, aligning the
corner edges.
6. The cover was cauterized to the membrane and base using the side
portions of the cautery pen at the three points shown in FIG.
7B.
Example 2: Cell Viability and Epithelial Growth Factor (EGF)
Content of Membranes
Samples were prepared as described in Example 1. After at least 48
hours of deep freezing in a -80.degree. C. freezer, batches of 8
samples were taken out and thawed in a room temperature water bath
18-24.degree. C. and tested to ensure minimum cell viability
(>70%) and for the amniotic membrane, EGF contents (>7.8
pg/ml). Results are shown in Tables 11-13 described herein.
Tissue samples of appropriate size (5.times.5 cm or 2.times.2 cm)
were used for validation assays. Refer to Table 1 for the number of
membranes to be tested per lot and the tests performed (Eastman
Tritan MP100 Copolyester (Tritan.TM.).
TABLE-US-00001 TABLE 1 Amniotic and Chorionic Membrane Testing
Scheme Amniotic membrane Chorionic Membrane Test Method
Nitrocellulose Tritan .TM. Nitrocellulose Tritan .TM. Cell
Viability Cell 1-5 cm .times. 5 cm 1-5 cm .times. 5 cm 1-5 cm
.times. 5 cm 1-5 cm .times. 5 cm count EGF ELISA 2-2 cm .times. 2
cm 2-2 cm .times. 2 cm N/A N/A concentration
Cell counts were performed. Briefly, amniotic membrane was digested
with collagenase and chorionic membrane was digested with
collagenase and trypsin for 15-45 min at 37.degree. C. with
constant agitation. Once tissue was completely digested or it
reached the longest time point, the cell suspension is either
passed through a cell strainer and wash strainer with Dulbecco's
Modified Eagle Medium (DMEM) (chorionic membrane) or centrifuged
and the cell/tissue pellet resuspended in trypsin and incubated at
37.degree. C. for another 5-15 min. After incubation the cell
suspension is passed through a cell strainer and wash strainer with
DMEM (amniotic membrane). Centrifuge for another 10 min to obtain
cell pellets. DMEM was added and cell counting performed using a
hemocytometer with Trypan blue exclusion under a light microscope.
Digested amniotic or chorionic samples were diluted to the
appropriate ratio in Trypan Blue and the number of cells in 5x
0.0001 ml squares were counted.
Human EGF ELISA assay was performed to measure the contents of
human EGF of amniotic membrane. Briefly, two 2.times.2 cm tissues
were used. Membrane was snap frozen in liquid nitrogen for 5
minutes. 500 .mu.l of calibrator diluents was added and the tissue
was homogenized in a Tissue Lyser chamber for 3 minutes at 50 Hz.
Samples were centrifuged at 14,000 rpm for 10 minutes at 4.degree.
C. The supernatant was used for ELISA assay. The assay is described
in details in manufacturer manual. Three lots of human amniotic
membrane were randomly selected and assayed.
Example 3: Evaluation Methods of Different Base Configurations
Mounted membranes were inspected for attachment with the packaging.
The passing criteria included that 1) all components of the
mounting applicator (the support assembly) and tissue stay
together; and 2) at least 75% of the tissue should stay flat on the
mounting applicator for all the following procedures:
Rinsing in Dulbecco's Modified Eagle Medium (DPBS)
Forceps were used to hold a corner of the base without touching the
mounted membrane. The membrane was rinsed in saline solution. The
membrane was monitored for detachment from the base.
Filling of the Cryoprotectant Solution
The membrane assembled within the base and cover (as in Example 1)
was placed into an OSRSFP-90 Cryogenic Storage bag. The bag was
filled with 50 ml cryoprotectant solution. The membrane was
monitored for detachment from the plastic base, and the cover was
monitored for detachment from the membrane and/or plastic base.
Rinsing Post-Thawed
After at least 18 hours of deep freezing at -80.degree. C.,
amniotic membrane was thawed in sufficient volume of room
temperature saline (such that the liquid surface could cover the
entire Cryogenic Storage bag) until all ice crystals disappeared.
The membrane was monitored for detachment from the plastic base
during thawing. Once thawed, the membrane was removed from the
OSRSFP-90 Cryogenic Storage bag and placed in the rinse basin
containing sterile saline. The membrane was monitored during
rinsing for detachment from the base and the cover was monitored
for detachment from the membrane and/or plastic base.
Application
The cover was removed and the tissue was observed to determine if
more than 75% of the tissue stayed attached to the base. The
membrane was promptly applied onto the wound such that its
orientation was maintained throughout the process.
Example 4: Non-Nitrocellulose Approaches
Coated nitrocellulose was found to introduce chemicals of animal
origins into subjects, thereby rendering the coated nitrocellulose
unsuitable for some patients. Non-nitrocellulose approaches were
therefore evaluated.
For the prototypes developed under this category, plastics were
identified as a material that provided for easy application in that
membranes and tissues can slide off the plastic onto the wound bed
while maintaining their orientation. This configuration included
two plastic pieces generally identified as a "cover" and a "base".
The base was used to maintain the orientation of the tissue,
includes a portion having a non-uniform surface (a tissue/membrane
receiving portion), and provides a platform for the sliding
application. The cover provides protection for the tissue/membrane
during manufacturing, transport, storage, and use (e.g., thawing).
The cover can minimize the fluid shear stress acting on the
epithelial layer of the tissue (membrane) during the filling of the
cryopreservation solution as well as during the transit and
handling of the cryogenic storage bags to/from a refrigerator into
a deep freezer. Different chemical and mechanical
fixation/attachment methods have been evaluated for the base and
are summarized in Table 2 (below). The perforation sandwich plastic
design was selected for further development as it passed all
evaluation criteria listed in Example 3
TABLE-US-00002 TABLE 2 Description of non-nitrocellulose paper
prototypes and their evaluation results. Prototype name Prototype
description Poly-D-Lysin- Coat plastic with 1 mg/ml Poly-D- treated
plastic Lysin solution for 3 hrs at 37.degree. C. Place amnion onto
the coated plastic with stromal side facing plastic. Incubate at
37.degree. C. for 3 hrs Sandpaper- Plastic were treated with
treated Plastic sandpaper. The entire surface feels rough to touch.
Microplate Sandwich the tissue in between the Devices two parts of
a Microplate Uniseal, UniSeal .TM. which contain an adhesive-backed
clear polyetyrene seal film and a water-resistant paper. 4 pins Fix
four corners of tissue samples with pins so it stretches out to a
square shape 4 straight slit Cut four corners of the base piece
corners into slits, then insert each corner of the tissue inside
the slits 4 straight slit Cut four corners of the base into corners
with hard slits; align tissue onto a piece of paper inserts thick
paper (blue) that was cut to the size of the units, i.e. 5 .times.
5 (cm.sup.2) or 2 .times. 2 (cm.sup.2); then tuck the paper with
the tissue inside the slits Two straight slits Cut two angled slits
on the base on the base with sheet to anchor the tissue. Cut two
cover piece corners parallel to the first two slits sealed together
on the plastic cover. Seal two with base plastic sheets together
shown as the grey line. Place the tissue on the base sheet and tuck
two base corners inside the two slits 4 clipping round Create four
corners of the base corners piece to half-moon shape using a 3 mm
biopsy punch; then tuck tissue in; tighten the tissue by pressing
the back side of the opening until hearing a click sound Frame with
Make a paper frame the same size plastic lamination as the units,
i.e. 5 .times. 5 (cm.sup.2) or 2 .times. 2 (cm.sup.2); lay it on
the top of one piece of plastic; then insert tissue samples inside
the frame; put another piece of same size plastic to enclose
everything; laminate the four sides Clamp The tissue membrane is
fastened in between two parts of the clamp and fastened by the
screw Plastic Holes (5 mm in diameter) were "Sandwich" with punched
using a comb hole perforations puncher paper binder binding
machine
Plastic Selection
Based on general performance of the above described embodiments,
the plastic "sandwich" configuration was selected for further
evaluation. The next step was to identify plastic that: is
compatible with living tissue, low temperature, and DMSO; and
complies with USP class VI testing (for plastics)
Copolyesters and polycarbonates were considered as potential
materials for development. Tritan is described in the examples
below as it was provided in a convenient validation package.
Example 5: Testing of Perforated Sandwich Design on Tritan.TM.
Sheets
Perforation Parameters
Sizes of the perforations and center-to-center spacing between
adjacent perforations were varied (Table 3). Four combinations of
perforation size and center-to-center spacing were chosen as listed
in Table 3. Placental membranes, either amniotic or chorionic
membrane, were mounted on perforated plastic and evaluated
according to performance criteria described in Example 3 including:
Rinsing in DPBS; Filling of the Cryoprotectant solution; Rinsing
post-thawed; and Application.
TABLE-US-00003 TABLE 3 Perforation parameters testing scheme
Perforation Center-to-Center Diameter Spacing 4 mm 10 mm 2 mm 10 mm
2 mm 5 mm 1 mm 4 mm
Neiko Hand Held Power Punch kit or a 1 mm biopsy punch was used to
manually create the perforations. AutoCAD file was generated and an
evenly distributed perforation design was printed onto the
Tritan.TM. sheet for easy tracing. 2 mm and 4 mm were selected
because perforation configuration with 5 mm holes was not able to
pass the visual inspection criteria listed. The schematic
representations of the perforation design and results are
summarized in Table 4.
The results show placental tissue mounted on Tritan.TM. sheet with
1 mm perforation spaced 4 mm apart meet all criteria listed.
Therefore these perforation size and spacing parameters were
selected for further cell viability and EGF testing.
TABLE-US-00004 TABLE 4 Effect of perforation size and
center-to-center spacing between perforations on amniotic membrane
handling properties. Schematic of perforation Prototype Results
FIG. 10A Bond between amniotic membrane and plastic resulted in
slightly compromised quadrant shape due to relatively weaker bond
between the plastic and amniotic membrane FIG. 10B Bond between
amniotic membrane and plastic resulted in slightly compromised
quadrant shape due to relatively weaker bond between the plastic
and amniotic membrane FIG. 10C Bond between amniotic membrane and
plastic maintains the square shape, however >30% of amniotic
membrane samples were detached from the plastic. FIG. 10D Bond
between amniotic membrane and plastic maintains the square shape.
<25% of amniotic membrane samples detached from the plastic
Example 6: Evaluation of Different Perforation Patterns on the
Tritan.TM. Sheet
Because the high number of holes potentially leads to higher
manufacturing cost, we sought to test whether different perforation
pattern design would allow us to reduce the number of holes needed
to provide strong bonding (maintain shape and attachment).
1 mm diameter was used and different perforation patterns were
tested as described in Table 5. AutoCAD files of the pattern were
generated and printed onto Tritan.TM. sheets. Holes were created
using 1 mm biopsy punches according to the printed design. Amniotic
membrane was then mounted onto the plastic. Top solid plastic
pieces were used to cover amniotic membrane mounted on the
perforated plastic. The evaluation of each pattern was done based
on the criteria listed above. The evaluation of each pattern was
done based on the criteria described in Example 3, including:
Rinsing in DPBS; Filling of the Cryoprotectant solution; Rinsing
post-thawed; and Application.
Results are summarized in Table 5. None of the described designs
provided results that were as effective as the most effective
patterns in Table 4.
TABLE-US-00005 TABLE 5 Effect of perforation pattern on the ability
to maintain more than 75% membrane on the base after removal of the
cover Schematic representation Number of of perforation pattern
perforations FIG. 11A 40 FIG. 11B 64 FIG. 11C 70
Example 7: Evaluation of Perforations on the Front or Back or Both
Pieces of the Plastic
Different combinations of the perforated and solid plastic pieces
were tested. In our hands the combination of the solid plastic
cover and the perforated plastic base allows the good attachment of
amniotic membrane with easy removal of the cover without
lifting/detaching amniotic membrane from the base. Results are
summarized in Table 6.
TABLE-US-00006 TABLE 6 Comparison between different perforation
positions Configuration Comments Perforation on the amniotic
membrane tends to cover only adhere to the cover Perforations on
Could not consistently keep both cover and more than 75% membrane
on base the base Perforations on The cover was easy to be the base
only removed amniotic membrane attaches well to the plastic
base
Example 8: Different Cautery Systems and Cautery Patterns
The improved two-piece packaging system embodiments are suitably
held together with the tissue to provide as one unit to the
customers. Here we investigated different cautery systems and
cautery patterns as the fixing method so that the chosen cautery
system and pattern 1) can effectively fix the tissues as well as
the two plastic pieces together without breaking apart; 2) avoid
burned brown spots of the tissue; and 3) is cost-effective and can
be used in a cleanroom environment.
Cautery Systems
Different cautery systems were evaluated as seen in Table 7. The
maximum number of cautery points for each system was recorded. The
performance criteria were described in Example 3. The Bovine Fine
Tip Cautery (704.degree. C.) configuration and the Bovine Vasectomy
Micro Fine Tip Cautery configuration were found to provide the best
performance and be the most economical. The other configurations
were found to have higher costs, provide fewer cautery points,
produce more burned products, or have a tendency to catch fire.
TABLE-US-00007 TABLE 7 Comparison Between Different Cautery Systems
Number of Configuration Cauterizations Gemini Cautery Kit N/A Bovie
Micro Fine Tip 31~54 Cautery, 454.degree. C. Accu-temp 1/2'' shaft
27 with fine tip, 677.degree. C. Bovie Fine Tip 99~168 Cautery,
764.degree. C. Bovie Vasectomy 90 Micro Fine Tip Cautery,
871.degree. C. Bovie Vasectomy N/A Micro Fine Tip Cautery,
982.degree. C. Accu-Temp Vasector N/A Fine Tip Cautery, 982.degree.
C. Bovie Micro Fine Tip 464 Cautery, 1093.degree. C. Bove Fine Tip
N/A Cautery, 816-1149.degree. C. Bove Fine Tip N/A Cautery,
1204.degree. C.
Cautery Patterns
Different cautery patterns were evaluated for amniotic membrane as
seen in Table 8A and chorionic membrane as seen in Table 8B. The
goal for these embodiments was to use the least number of cautery
points to meet all performance criteria.
Design 1 (with eight points) was found to work best for amniotic
membrane, with five points on the base and three points on the
cover. For chorionic, Design 1 was found to work the best, with six
points on the base and three points on the cover. In order to
simplify the manufacturing process, it is contemplated that Design
1 for the chorionic membrane can be used to support both placental
membranes.
For the amniotic membrane experiment, Designs 2-9 either did not
consistently meet the performance criteria or were found to have
too many cautery points (resulting in an overly complicated
manufacturing process). Similarly, for the chorionic membrane
experiment, Designs 2-9 either did not consistently meet the
performance criteria or were found to have too many cautery points
(resulting in an overly complicated manufacturing process).
However, it is contemplated that Designs 2-9 for the amniotic
membrane experiment and Designs 2-9 for the chorionic membrane
experiment can be used as disclosed herein to support a membrane or
other biological product.
TABLE-US-00008 TABLE 8A Cautery patterns for amniotic membrane #
cautery Number Schematic Diagram points 1 FIG. 12A 8 2 FIG. 12B 7 3
FIG. 12C 6 4 FIG. 12D 8 5 FIG. 12E 8 6 FIG. 12F 9 7 FIG. 12G 9 8
FIG. 12H 13 9 FIG. 12I 12
TABLE-US-00009 TABLE 8B Cautery patterns for chorionic membranes #
of Design Cautery Number Schematic Diagram Points 1 FIG. 13A 9 2
FIG. 13B 8 3 FIG. 13C 8 4 FIG. 13D 8 5 FIG. 13E 7 6 FIG. 13F 9 7
FIG. 13G 9 8 FIG. 13H 8 9 FIG. 13I 6
Example 9: Effect of New Plastic Packaging on Placental
Products
Results in Table 9-11 demonstrated that the plastic packaging has
no negative effect on cell viability for both membranes (amniotic
and chorionic) and EGF content for amniotic membranes.
Effect of New Plastic Packaging on Cell Viability of Placental
Membranes
TABLE-US-00010 TABLE 9 Evaluation of cell viability of amniotic
membrane on Tritan .TM. Assay Acceptance Donor Conditions Cell
Viability (>70%) 1 Control 77% Pass Tritan .TM. 70% Pass 2
Control 79% Pass Tritan .TM. 73% Pass 3 Control 71% Pass Tritan
.TM. 78% Pass 4 Control 78% Pass Tritan .TM. 73% Pass 5 Control 94%
Pass Tritan .TM. 90% Pass 6 Control 87% Pass Tritan .TM. 84%
Pass
TABLE-US-00011 TABLE 10 Cell Viability of chorionic membrane Assay
Donor Cell Acceptance Information Conditions Viability (>70%) 7
Control 81% Pass Tritan .TM. 87% Pass 8 Control 86% Pass Tritan
.TM. 79% Pass 9 Control 81% Pass Tritan .TM. 89% Pass
Effect of New Plastic Packaging on EGF Content of Amniotic
Membrane
TABLE-US-00012 TABLE 11 Evaluation of EGF contents of amniotic
membrane on Tritan .TM. by ELISA EGF Assay Donor Concentration
Acceptance Information Conditions (pg/ml) (>78 pg/ml) 10 Control
109.5 Pass Tritan .TM. 157.3 Pass 11 Control 33.3 Pass Tritan .TM.
43.5 Pass 12 Control 95.6 Pass Titan .TM. 69.6 Pass
Thus, as exemplified by the above-described illustrative
embodiments, a mounting applicator (support assembly) has been
designed for membrane and tissues that can be derived from natural
or non-natural (i.e., synthetic) sources. The applicator (support
assembly) can replace current technology based on nitrocellulose
paper and provides a simple application procedure for the end user.
As further disclosed herein, the applicator (support assembly) can
comprise a cover and a base, suitably of a plastic material, that
are positioned to accept a membrane between the cover and base. The
base has an irregular surface, such as a perforated portion, which
receives a membrane, having a size generally corresponding to its
cover, and a tab area for handling purposes. The base can be sealed
to the tissue (e.g., membrane to base) at a plurality of points,
and additional seal points can secure the cover to the membrane
and/or base to make a "sandwich" configuration.
Example 10: Method of Thawing and Application of a Cryopreserved
Membrane Product of the Present Technology
Placental membrane products can be cryopreserved and stored frozen
and shipped to the end user in a Styrofoam container.
Thawing:
Prior to use of the placental membrane product, two basins, a
bottle of sterile saline, scissors, sterile forceps and gloves can
be gathered. One large basin can be used for thawing and a smaller
sterile basin for rinsing.
The placental membrane product can be removed from storage. The
placental product can be packaged in a carton box with tamper
evident labels on each side of the box which describe product name
and size, lot number, unit number, date of expiry, part number and
required storage conditions. Inside the box, the product can be
provided in a chevron-type peel pouch, along with the package
insert and chart labels to be used on the patient's records.
The outer pouch can be peeled open and the inner cryobag can be
placed into the large thaw basin. To ensure the orientation of the
placental product is correct, the cryobag can be be placed in the
thaw basin with the label side up so it is visible to read.
Sufficient warm water or saline can be added into the large thaw
basin containing the placental product to completely cover the
cryobag. The water temperature should not exceed about 39.degree.
C. or 102.degree. F.
While the product is thawing, sterile saline can be added to the
small rinse basin. Once all ice crystals are completely thawed, the
placental product (graft) can be removed from the cryobag. The
placental product should remain in the thaw basin for no more than
15 minutes. Holding the cryobag with the port side down, the top of
the bag can be cut with sterile scissors, taking care not to cut
near the graft. With sterile forceps, the placental product (graft)
can be removed from the cryobag.
In an operating room setting, sterile tools and basins should be
used, and aseptic technique should be applied when thawing the
placental product.
Next, the placental product can be placed into the sterile rinse
basin and confirm that the lettering on the base is oriented
correctly (e.g., the base correctly reads "PRIME" or "CORE" as
shown in FIGS. 6A and 7A). This can allow for correct orientation
for placement onto a wound, for example, for amniotic membranes.
The membrane should be applied to the subject or patient within one
hour.
Application:
The index wound identified for placental membrane placement should
be appropriately cleaned and debrided.
To apply the placental product, the base can be held on the labeled
tab, and the top plastic cover can be removed. Once the cover is
off, the placental product can be slid from the plastic backing
onto the wound bed using aseptic technique.
Next, using sterile forceps, sterile gloves, or sterile moist
cotton applicators, the graft can be maneuvered to ensure that the
entire wound bed is covered. The graft should be in direct contact
with all surfaces of the wound bed, including the edges.
Excess membrane can be placed on the edges of the wound, can extend
over the surrounding healthy tissue, or can be folded into the
wound bed. Any air bubbles and pockets that may exist between the
graft and the wound should be removed for best results.
The placental product can optionally be covered with a non-adherent
dressing, and an appropriate compressive or outer layer dressing
can be applied, depending on wound type.
Example 11: Comparison of Thawing Time for Placental Tissue Mounted
on Either Disclosed Support Assembly (Tritan.TM.) or Nitrocellulose
Paper
Objective: To investigate whether there is a significant reduction
of thawing time when using the disclosed support assembly (base and
cover), the current thawing procedures were performed on placental
membrane mounted on the disclosed support assembly and on
nitrocellulose paper.
Methods:
Two samples were taken from two lots of placental tissue, with one
sample of each lot packaged in the disclosed support assembly and
the other sample of each log packaged on nitrocellulose paper. All
samples were removed from the deep freezer (-80.degree. C.).
A cryobag containing the placental tissue was positioned in the
thawing basin, which was filled with room temperature water.
Record Thawing Time
For placental tissue on nitrocellulose paper, the timer was stopped
when all ice crystals were not visible.
For placental tissue on the support assembly disclosed herein, the
timer was stopped when the plastic of the support assembly could be
separated from its surrounding ice crystals.
TABLE-US-00013 TABLE 12 Results: Thawing Time (min) Donor
Nitrocellulose paper Tritan .TM. A 24 3 B 28 4
Because of the unique packaging design (plastic-membrane-plastic
"sandwich") of the disclosed support assembly, when thawing is
sufficient to loosen surrounding ice crystals, it is safe to take
the support assembly out of the bag and simply remove the ice
chunks on either side of the plastic without damaging the membrane
enclosed in between.
In contrast, for placental tissue mounted on nitrocellulose paper,
the thawing had to be complete, i.e. all ice crystals disappear.
Otherwise, the weight of the ice could tear the membrane or cause
the membrane to fall off of the nitrocellulose paper, leading to
self-folding when thawing is complete.
Conclusion: The disclosed plastic packaging allowed a 8-10 times
faster thawing time than conventional nitrocellulose paper
packaging.
Exemplary Devices, Methods, and Kits
In various exemplary aspects, disclosed herein is a support
assembly for supporting a biological product in an operative
position, the support assembly comprising: a base having a
longitudinal axis and comprising a product receiving portion, the
product receiving portion having a top surface and an opposed
bottom surface that are spaced apart relative to a vertical axis
that is perpendicular to the longitudinal axis of the base, wherein
the product receiving portion comprises an traction-creating
feature, wherein the traction-creating feature is selected from the
group consisting of (i) a rough top surface and (ii) a plurality of
perforations extending between the top and bottom surfaces of the
product receiving portion; and a cover having a longitudinal axis,
a top surface, and an opposed bottom surface, wherein the cover is
configured for releasable coupling to the base in a
product-covering position, and wherein, in the product-covering
position, the cover overlies the product receiving portion of the
base, wherein the base and the cover are configured to cooperate to
support the biological product in the operative position, wherein,
in the operative position, the biological product is positioned in
engagement with at least a portion of the top surface of the
product receiving portion of the base and at least a portion of the
bottom surface of the cover.
In another exemplary aspect, the base further comprises a handling
portion positioned adjacent to the product receiving portion
relative to the longitudinal axis of the base. In another exemplary
aspect, in the product-covering position, the cover does not
overlap with the handling portion of the base. In another exemplary
aspect, the handling portion comprises a tab. In another exemplary
aspect, the handling portion of the base has a longitudinal length
and a width, wherein the product receiving portion of the base has
a longitudinal length and a width, and wherein the width of the
product receiving portion is equal to the width of the handling
portion.
In another exemplary aspect, in the product-covering position, the
longitudinal axis of the cover is positioned in substantial
alignment with the longitudinal axis of the base. In another
exemplary aspect, the product receiving portion of the base has a
longitudinal length and a width, wherein the cover has a
longitudinal length and a width, and wherein the longitudinal
length of the cover is substantially equal to the longitudinal
length of the product receiving portion. In another exemplary
aspect, the width of the cover is substantially equal to the width
of the product receiving portion.
In another exemplary aspect, the cover has a plurality of corners,
and at least one of the corners of the cover is rounded. In another
exemplary aspect, the cover has four rounded corners. In another
exemplary aspect, the product receiving portion of the base has two
rounded corners, and wherein, in the product-covering position, two
rounded corners of the cover overlie the two rounded corners of the
product receiving portion of the base.
In another exemplary aspect, the traction-creating feature of the
product receiving portion of the base comprises a plurality of
perforations. In another exemplary aspect, the plurality of
perforations of the product receiving portion of the base are
substantially evenly distributed throughout the product receiving
portion. In another exemplary aspect, the plurality of perforations
of the product receiving portion of the base are randomly
distributed throughout the product receiving portion. In another
exemplary aspect, each perforation of the plurality of perforations
has a respective diameter ranging from about 0.1 mm to about 5 mm.
In another exemplary aspect, each perforation of the plurality of
perforations has a respective center point, and wherein the center
points of neighboring perforations are spaced apart by a distance
ranging from about 0.35 mm to about 10 mm.
In another exemplary aspect, the traction-creating feature of the
product receiving portion of the base comprises a rough top
surface.
In further exemplary aspects, the disclosed support assembly can be
provided as part of a membrane product package, which further
comprises a membrane positioned in an operative position between
the product receiving portion of the base and the cover, wherein
the membrane is positioned in engagement with at least a portion of
the top surface of the product receiving portion of the base and at
least a portion of the bottom surface of the cover.
In another exemplary aspect, the membrane is attached to the top
surface of the product receiving portion of the base at at least
one attachment point. In another exemplary aspect, the membrane is
attached to the top surface of the product receiving portion of the
base at at least three attachment points. In another exemplary
aspect, the membrane is attached to the top surface of the product
receiving portion of the base at at least five attachment points.
In another exemplary aspect, the top surface of the product
receiving portion of the base is attached to the cover at at least
one attachment point.
In another exemplary aspect, the cover is attached to the membrane
at at least one attachment point. In another exemplary aspect, the
cover is attached to the membrane at at least two attachment
points. In another exemplary aspect, the cover is attached to the
membrane at at least three attachment points. In another exemplary
aspect, the top surface of the product receiving portion of the
base is attached to the cover at at least one attachment point.
In another exemplary aspect, the top surface of the product
receiving portion of the base is attached to the cover at at least
one attachment point. In another exemplary aspect, the top surface
of the product receiving portion of the base is attached to the
cover at at least three attachment points.
In another exemplary aspect, the attachment points between the base
and the membrane, between the cover and the membrane, and/or
between the base and the cover are cauterization points.
In another exemplary aspect, the membrane is a natural
membrane.
In another exemplary aspect, the membrane is a placental tissue
product. In another exemplary aspect, the membrane is a chorionic
membrane product. In another exemplary aspect, the membrane is an
amniotic membrane product.
In another exemplary aspect, the membrane is a synthetic
membrane.
In another exemplary aspect, the membrane and the top surface of
the product receiving portion of the base have sufficient surface
traction to maintain the membrane in the operative position
following removal of the cover from the base.
In another exemplary aspect, the membrane and the top surface of
the product receiving portion of the base have a first surface
traction, wherein the membrane and the cover have a second surface
traction, and wherein the second surface traction is lower than the
first surface traction.
In additional exemplary aspects, the disclosed support assembly can
be used in a method of producing a membrane product package, the
method comprising positioning a membrane in an operative position
between the product receiving portion of the base and the cover of
the support assembly, wherein the membrane is positioned in
engagement with at least a portion of the top surface of the
product receiving portion of the base and at least a portion of the
bottom surface of the cover.
In another exemplary aspect, the step of positioning the membrane
in the operative position comprises: attaching the membrane to the
top surface of the product receiving portion at a plurality of
attachment points; and attaching the membrane to the cover at a
plurality of attachments points. In another exemplary aspect, when
the traction-creating feature of the product receiving portion
comprises a plurality of perforations, the method further comprises
positioning the base, the membrane, and the cover within a
cryopreservation solution, wherein the plurality of perforations of
the product receiving portion provide contact between the membrane
and the cryopreservation solution sufficient to cryopreserve the
membrane.
In further exemplary aspects, a method of applying a membrane is
provided, comprising removing the cover from the disclosed membrane
product package to expose a top surface of the membrane;
disengaging the membrane from the top surface of the product
receiving portion of the base; and selectively applying the
membrane to a desired location on a human or animal patient.
In still further exemplary aspects, the disclosed membrane product
package can be provided as part of a kit for repairing a tissue
defect. In another exemplary aspect, the kit can further comprise a
container that encloses the membrane product package, wherein the
container can be selectively opened to provide access to the
membrane product package. In another exemplary aspect, the kit can
further comprise instructions for applying the membrane of the
membrane product package to repair the tissue defect. In still
further exemplary aspects, the kit can further comprise a
cryopreservation solution. In still further exemplary aspects, the
kit can further comprise a basin configured to receive the membrane
product package. In still further exemplary aspects, the kit can
further comprise scissors. In still further exemplary aspects, the
kit can further comprise tweezers.
More generally, in further exemplary aspects, disclosed herein is a
device (e.g., a support assembly) comprising: a base comprising a
product (e.g., membrane) receiving portion; and a cover; and at
least one location in which the base and the cover are in
communication (at least one temporary or removable attachment
between the back and the cover.
In another exemplary aspect, the membrane receiving portion
comprises a traction-creating feature (e.g., a structured surface).
In another exemplary aspect, the traction-creating feature (e.g.,
structured surface) is selected from the group consisting of an
abraded surface, a rough surface, a scratched surface, a surface
comprising a plurality of perforations; a surface comprising a
plurality of channels; a surface comprising a plurality of grooves;
a surface comprising a plurality of indentations.
In another exemplary aspect, the traction-creating feature (e.g.,
structured surface) of the membrane receiving portion comprises a
surface comprising a plurality of perforations. In another
exemplary aspect, the plurality of perforations are uniformly
distributed throughout the membrane receiving portion. In another
exemplary aspect, the plurality of perforations are randomly
distributed throughout the membrane receiving portion. In another
exemplary aspects, the plurality of perforations are evenly
distributed in close relationship to each other throughout the
membrane receiving portion to provide sufficient surface traction
for the membrane to adhere to the base. In another exemplary
aspect, the plurality of perforations are about 1 mm to about 5 mm
in diameter and each perforation is from 4 mm to about 10 mm apart
as measured center to center. In another exemplary aspect, the
plurality of perforations are from about 0.1 mm to about 5 mm in
diameter. In another exemplary aspect, the plurality of
perforations are from about 0.1 mm to about 1 mm in diameter. In
another exemplary aspect, the perforations are spaced about 0.35 mm
to about 10 mm apart as measured center to center. In another
exemplary aspect, the perforations are spaced about 4 mm to about
10 mm apart as measured center to center. In another aspect, the
plurality of perforations are of a geometrical shape or a
nongeometrical shape. In another exemplary aspect, the plurality of
perforations are a shape selected from the group consisting of
oval, rectangular, square, diamond, trapezoid, star, hexagonal,
octagonal, semi-circular, crescent, or a combination thereof.
In another exemplary aspect, the traction-creating feature of the
membrane receiving portion comprises a rough plastic surface.
In another exemplary aspect, the base comprises at least one
plastic or polymer.
In another exemplary aspect, the cover comprises at least one
plastic or polymer.
In another exemplary aspect, the plastic base further comprises a
handling portion adjacent to the membrane receiving portion.
In another exemplary aspect, the handling portion does not overlap
with the cover.
In another exemplary aspect, the handling portion comprises a tab.
In another exemplary aspect, the tab spans the entire width of the
base.
In another exemplary aspect, the cover spans the entire membrane
receiving portion of the base.
In another exemplary aspect, the at least one location in which the
base and cover are in communication comprises at least one
cauterization point, at least one point made by an ultrasonic
welder, or at least one point comprising an adhesive. In another
exemplary aspect, the at least one location in which the base and
cover are in communication comprises a plurality of points.
In another exemplary aspect, the base and the plastic cover are
formed from a single piece of plastic.
In another exemplary aspect, the base and the plastic cover are
separate pieces of plastic.
In another exemplary aspect, the base and the cover are made of the
same plastic.
In another exemplary aspect, base comprises plastic selected from
the group consisting of polycarbonate, copolyester, low density
polyethylene (LDPE), high density polyethylene (HDPE), ECTFE
copolymer, ETFE copolymer, FEP (fluorinated ethylene propylene), PE
(Polyethylene), PP (Polypropylene), PMP (Polymethylpentene),
Teflon, PS (Polystyrene), EVA, and Tritan copolyester MP100.
In another exemplary aspect, the plastic of the cover is selected
from the group consisting of polycarbonate, copolyester, low
density polyethylene (LDPE), high density polyethylene (HDPE),
ECTFE copolymer, ETFE copolymer, FEP (fluorinated ethylene
propylene), PE (Polyethylene), PP (Polypropylene), PMP
(Polymethylpentene), Teflon, PS (Polystyrene), EVA, and Tritan
copolyester MP100.
In another exemplary aspect, the cover is a solid sheet of
plastic.
In another exemplary aspect, the cover has non-sharp corners. In
another exemplary aspect, the corners are rounded.
In another exemplary aspect, the base has non-sharp corners. In
another exemplary aspect, the base has rounded edges.
In another exemplary aspect, the cover has four rounded
corners.
In another exemplary aspect, the device reduces damage to a
membrane during cryopreservation. In another exemplary aspect, the
device is sufficient to reduce damage to a membrane due to fluid
shear force during addition or submersion into cryopreservation
solution.
In another exemplary aspect, the device provides sufficient
permeation of the cryopreservation solution to a membrane.
In another exemplary aspect, the device retains its integrity when
immersed in a cryopreservation solution.
In another exemplary aspect, the device retains its integrity
during a freeze-thaw cycle. In another exemplary aspect, the freeze
thaw cycle includes a freezing step of about -45.degree. C. to
-196.degree. C. for a cellular membrane and about -18.degree. C. to
about -196.degree. C. for an acellular membrane.
In another exemplary aspect, the cover is the same size as the
membrane receiving portion of the base.
In another exemplary aspect, the base and cover are free of
impurities. In another exemplary aspect, the base and cover are
free of particulates or oils or other chemicals that may interfere
with the viability or therapeutic efficacy of the membrane.
In another exemplary aspect, the at least one location in which the
base and the cover are in communication comprises a plurality of
points. In another exemplary aspect, the plurality of points
comprise a plurality of cauterization points, wherein the plurality
of cauterization points comprises at least two cauterization
points, preferably at least three cauterization points.
In another exemplary aspect, the at least one location in which the
base and cover are in communication allows for the retention of the
cover to the base through a cryopreservation step, a freezing step
and a thawing step.
In another exemplary aspect, a membrane is between the base and the
cover. In another exemplary aspect, the membrane is attached to the
base by at least three points. In another exemplary aspect, the
membrane is attached to the base by at least five points. In
another exemplary aspect, the membrane is attached to the base by
at least six points. In another exemplary aspect, the cover is in
communication with the base at least at two points. In another
exemplary aspect, the cover is in communication with the base at
least at three points. In another exemplary aspect, the membrane is
a selected from the group consisting of a natural membrane, a
synthetic membrane or a combination thereof. In another exemplary
aspect, the membrane is a natural membrane. In another exemplary
aspect, the membrane is a placental tissue product. In another
exemplary aspect, the membrane is a synthetic membrane. In another
exemplary aspect, the membrane is a combination of natural and
synthetic membrane. In another exemplary aspect, the membrane is
bioengineered. In another exemplary aspect, the membrane is a
chorionic membrane product. In another exemplary aspect, the
membrane is an amniotic membrane product. In another exemplary
aspect, the membrane is an in vitro derived tissue. In another
exemplary aspect, the membrane is a cultured tissue equivalent.
In another exemplary aspect, the device withstands freezing at
about -80.degree. C. to about -196.degree. C. without losing
integrity.
In another exemplary aspect, the device is resistant to chemical or
physical alteration by cryopreservation solutions. In another
exemplary aspect, the cryopreservation solution comprises DMSO.
In another exemplary aspect, the membrane receiving portion is
about 1.5 cm.times.1.5 cm, about 2 cm.times.3 cm, about 3
cm.times.4 cm, or about 5 cm.times.5 cm.
In another exemplary aspect, the device allows for sufficient
contact between the membrane and the cryopreservation solution to
sufficiently cryopreserve the natural membrane to maintain
viability. In another exemplary aspect, the viability is at least
70% after at least one freeze-thaw cycle in cryopreservation
solution. In another exemplary aspect, the membrane maintains
sufficient viability. In another exemplary aspect, the membrane has
at least 70% viability.
In another exemplary aspect, the base and the membrane have
sufficient surface traction to maintain the membrane on the
base.
In another exemplary aspect, the surface traction between the
membrane and the cover is lower than the surface traction between
the membrane and the base.
In another exemplary aspect, the plurality of perforations,
plurality of grooves, or plurality of channels is sufficient to
cryopreserve the membrane by providing contact between the membrane
and the cryopreservation solution.
In another exemplary aspect, the membrane receiving portion of the
base is about 1.5 cm.times.1.5 cm, about 1.5 cm.times.2.0 cm, about
2 cm.times.2 cm, about 2 cm.times.3 cm, about 3 cm.times.4 cm,
about 5 cm.times.5 cm, about 5 cm.times.7 cm, or about 7.5
cm.times.15 cm.
In another exemplary aspect, the handling portion comprises a label
to indicate orientation. In another exemplary aspect, the label to
indicate orientation is a word. In another exemplary aspect, the
label to indicate orientation is a symbol.
In further exemplary aspects, the disclosed device can be used in a
method of maintaining the directionality of a membrane during
storage, cryopreservation, or during application to a subject, the
method comprising: a) preparing a tissue, wherein the tissue is
orientated having a first and a second side, wherein the first and
second side comprise different composition; b) adhering the
membrane to the disclosed device, wherein the membrane is disposed
between the base and the cover, wherein the first side of the
membrane is facing the base and the second side of the membrane is
facing the cover, and wherein the device further comprises a label
to indicate orientation. In another exemplary aspect, the membrane
is a placental tissue. In another exemplary aspect, the first side
of the membrane comprises stromal cells and the second side
comprises epithelial cells. In another exemplary aspect, the first
side of the membrane has greater adherence to the base than the
second side of the membrane. In another exemplary aspect, the base
provides a handling portion that comprises the label to indicate
orientation. In another exemplary aspect, the label is a word. In
another exemplary aspect, the label is a symbol.
In still further exemplary aspects, the disclosed device can be
used in a method of maintaining integrity of a membrane during
cryopreservation, the method comprising: providing the disclosed
device; adhering a membrane to at least an area of the membrane
receiving portion of the base; adhering the cover to the base,
wherein the membrane is between the cover and the base; and placing
the device comprising the membrane into a container; and contacting
the container with sterile cryopreservation solution, wherein the
device comprising the membrane is submerged in the cryopreservation
solution; and cryopreserving the container at a temperature of
about -80.degree. C. to about -196.degree. C. for an membrane
containing cells and about -18.degree. C. to about -196.degree. C.
for an acellular membrane, wherein the integrity of the membrane is
maintained once the membrane is thawed to room temperature.
In additional exemplary aspects, the disclosed device can be
provided as part of a kit, which further comprises instructions for
adhering a membrane between the base and the cover of the device,
wherein the base and the cover have at least one location which is
adapted to be in communication with each other. In another
exemplary aspect, the kit further comprises an adhesive that is
biologically compatible. In another exemplary aspect, the
instructions further comprise a method of adhering the base to a
first side of the membrane, wherein the method comprises applying
the adhesive to at least one location between the base and the
membrane to form a membrane-covered base. In another The kit of
claim 156, wherein the instructions provide a method of adhering
the cover to base wherein the membrane is located between said
cover and base, wherein the method comprises applying the adhesive
to at least one point between the cover and the membrane-covered
base. In another exemplary aspect, the instructions further
comprise a step of cauterizing at least one point of the cover to
the base, wherein the membrane is located between the cover and
base. In another exemplary aspect, the instructions further
comprise a method of maintaining the directionality of the
membrane, the method comprising the steps of adhering a first side
of the membrane to the base. In another exemplary aspect, the kit
further comprises instructions for cryopreserving the device
comprising a membrane. In another exemplary aspect, the step of
cryopreserving comprises freezing the device containing the
membrane at -80.degree. C. In another exemplary aspect, the kit
further comprises instructions for thawing the cryopreserved
device. In another exemplary aspect, the kit further comprises
instructions of applying the membrane to a patient (human or
animal) in need thereof.
Exemplary Compositions, Methods, and Kits
In further exemplary aspects, disclosed is a composition
comprising: (a) a base comprising a membrane receiving portion; (b)
a membrane; (c) a cover; and (d) at least one location in which the
base and the cover are in communication, wherein the membrane is
positioned between the base and the cover.
In another exemplary aspect, the base further comprises a handling
portion. In another exemplary aspect, the handling portion is
adjacent to the membrane receiving portion. In another exemplary
aspect, the handling portion comprises a tab.
In another exemplary aspect, the membrane receiving portion
comprises a plurality of perforations. In another exemplary aspect,
the plurality of perforations are uniformly distributed throughout
the membrane receiving portion. In another exemplary aspect, the
plurality of perforations are randomly distributed throughout the
membrane receiving portion. In another exemplary aspect, the
plurality of perforations are evenly distributed in close
relationship to each other throughout the membrane receiving
portion to provide sufficient surface traction for the membrane to
adhere to the base. In another exemplary aspect, the plurality of
perforations are about 1 mm to about 5 mm in diameter and the each
perforation is from 4 mm to about 10 mm apart as measured center to
center. In another exemplary aspect, the plurality of perforations
are from about 0.1 mm to about 5 mm diameter. In another exemplary
aspect, the plurality of perforations are from about 0.1 mm to
about 1 mm diameter. In another exemplary aspect, the perforations
are spaced about 0.35 mm to about 10 mm apart as measured center to
center. In another exemplary aspect, the perforations are spaced
about 4 mm to about 10 mm apart as measured center to center. In
another exemplary aspect, the plurality of perforations are of any
geometrical shape or non-geometrical shape. In another exemplary
aspect, the plurality of perforations are a shape selected from the
group consisting of oval, rectangular, square, diamond, trapezoid,
star, hexagonal, octagonal, semi-circular, crescent, or a
combination thereof. In another exemplary aspect, the plurality of
perforations are sufficient to cryopreserve the membrane by
providing contact between the membrane and the cryopreservation
solution.
In another exemplary aspect, the base and the cover comprise a
single sheet of plastic. In another exemplary aspect, the single
sheet of plastic is folded to form a base and a cover.
In another exemplary aspect, the membrane receiving portion is
selected from the group consisting of an abraded surface, a rough
surface, a scratched surface, a surface comprising a plurality of
perforations; a surface comprising a plurality of channels; a
surface comprising a plurality of grooves; or a surface comprising
a plurality of indentations.
In another exemplary aspect, the base comprises at least one
plastic.
In another exemplary aspect, the cover comprises at least one
plastic.
In another exemplary aspect, the handling portion does not overlap
with the cover. In another exemplary aspect, the handling portion
spans the entire width of the base. In another exemplary aspect,
the cover spans the entire membrane receiving portion of the
base.
In another exemplary aspect, the base and the plastic cover are
separate pieces of plastic.
In another exemplary aspect, the plastic of the base is selected
from the group consisting of polycarbonate, copolyester, low
density polyethylene (LDPE), high density polyethylene (HDPE),
ECTFE copolymer, ETFE copolymer, FEP (fluorinated ethylene
propylene), PE (Polyethylene), PP (Polypropylene), PMP
(Polymethylpentene), Teflon, PS (Polystyrene), EVA, and Tritan
copolyester MP100.
In another exemplary aspect, the plastic of the cover is selected
from the group consisting of polycarbonate, copolyester, low
density polyethylene (LDPE), high density polyethylene (HDPE),
ECTFE copolymer, ETFE copolymer, FEP (fluorinated ethylene
propylene), PE (Polyethylene), PP (Polypropylene), PMP
(Polymethylpentene), Teflon, PS (Polystyrene), EVA, and Tritan
copolyester MP100.
In another exemplary aspect, the cover is a solid sheet of
plastic.
In another exemplary aspect, a first side of the cover is in
contact with a second side of the membrane and the first side of
the membrane is in contact with a first side of the base, and
wherein the first side of the cover has a lower surface tension
than a first side of the base.
In another exemplary aspect, the cover has no sharp corners or
edges. In another exemplary aspect, the corners are rounded.
In another exemplary aspect, the base has no sharp corners or
edges. In another exemplary aspect, the base has rounded
corners.
In another exemplary aspect, the composition is sufficient to
reduce damage to the membrane during cryopreservation. In another
exemplary aspect, the composition is sufficient to reduce damage to
the membrane due to fluid shear force during addition or submersion
into cryopreservation solution.
In another exemplary aspect, the composition retains its integrity
in a cryopreservation solution.
In another exemplary aspect, the composition retains its integrity
during a freeze-thaw cycle. In another exemplary aspect, the freeze
thaw cycle includes a freezing step of -40.degree. C. to
-196.degree. C. for a cellular membrane and -18.degree. C. to
-196.degree. C. for an acellular membrane.
In another exemplary aspect, the cover is the same size as the
membrane receiving portion of the base.
In another exemplary aspect, the base and cover are free from
impurities.
In another exemplary aspect, the base and the cover are free of
particulates or oils or other chemicals that may interfere with the
viability or therapeutic efficacy of the membrane.
In another exemplary aspect, the at least one location in which the
base and the cover are in communication comprises a plurality of
points. In another exemplary aspect, the plurality of points
comprise a plurality of cauterization points.
In another exemplary aspect, the at least one location in which the
base and cover are in communication allows for the retention of the
cover to the base through a cryopreservation step, a freezing step
and a thawing step.
In another exemplary aspect, the membrane is attached to the base
by at least three points. In another exemplary aspect, the membrane
is attached to the base by at least five points. In another
exemplary aspect, the membrane is attached to the base by at least
six points.
In another exemplary aspect, the cover is in communication with the
base and membrane at least at two points. In another exemplary
aspect, the cover is in communication with the base at least at
three points.
In another exemplary aspect, the membrane is a selected from the
group consisting of a natural membrane, a synthetic membrane or a
combination thereof.
In another exemplary aspect, the membrane is a natural
membrane.
In another exemplary aspect, the membrane is a placental tissue
product. In another exemplary aspect, the membrane is a chorionic
membrane product. In another exemplary aspect, the membrane is an
amniotic membrane product.
In another exemplary aspect, the membrane is a synthetic
membrane.
In another exemplary aspect, the membrane is a combination of
natural and synthetic membrane.
In another exemplary aspect, the membrane is bioengineered
membrane.
In another exemplary aspect, the membrane is an in vitro derived
tissue.
In another exemplary aspect, the membrane is a cultured tissue
equivalent.
In another exemplary aspect, the membrane is a graft.
In another exemplary aspect, the composition withstands freezing at
-80.degree. C. without losing integrity.
In another exemplary aspect, the composition is resistant to
chemical alteration by a cryopreservation solution. In another
exemplary aspect, the cryopreservation solution comprises DMSO.
In another exemplary aspect, the membrane receiving portion is 2
cm.times.2 cm. In another exemplary aspect, the membrane receiving
portion of the base is about 1.5 cm.times.1.5 cm, about 1.5
cm.times.2 cm, about 2 cm.times.2 cm, about 2 cm.times.3 cm, about
3 cm.times.4 cm, about 5 cm.times.5 cm, about 5 cm.times.7 cm, or
about 7.5 cm.times.15 cm.
In another exemplary aspect, the composition allows for sufficient
contact between the membrane and the cryopreservation solution to
sufficiently cryopreserve the natural membrane to maintain
viability.
In another exemplary aspect, the viability of the membrane is at
least 70% after at least one freeze-thaw cycle in cryopreservation
solution.
In another exemplary aspect, the base and the membrane have
sufficient surface traction to maintain the membrane on the base
when submerged in a solution.
In another exemplary aspect, the surface traction between a second
side of the membrane and the cover is lower than the surface
traction between a first side of the membrane and the base.
In another exemplary aspect, the membrane maintains sufficient
viability after cryopreservation. In another exemplary aspect, the
viability of the membrane is at least 70%.
In another exemplary aspect, the membrane is a graft.
In another exemplary aspect, the base or the cover is labeled to
indicate orientation. In another exemplary aspect, the label is
located on the base. In another exemplary aspect, the label is
located on a handling portion of the base. In another exemplary
aspect, the label is located on the cover. In another exemplary
aspect, the label is located on a handling portion adjacent to the
cover.
In further exemplary aspects, the disclosed composition can be used
in a method of applying a membrane to a patient (human or animal)
in need thereof, the method comprising: obtaining the disclosed
composition, wherein the composition has been cryopreserved and
frozen; thawing the composition; rinsing the membrane in a sterile
physiological solution; removing the cover from the membrane and
base; and applying the membrane from the base onto the patient
(human or animal) to retain directionality of the membrane.
In still further exemplary aspects, the disclosed composition can
be used in a method of treating a wound, the method comprising
applying a membrane of the composition to a patient in need
thereof.
In additional exemplary aspects, the disclosed composition can be
provided as a cryopreserved membrane composition, which further
comprises a cryopreservation solution. In another exemplary aspect,
the cryopreservation solution comprises DMSO. In another exemplary
aspect, the cryopreservation solution comprises about 5% DMSO. In
another exemplary aspect, the cryopreservation solution comprises
about 2% to about 10% DMSO. In another exemplary aspect, the
cryopreservation solution further comprises about 1% to about 20%
serum albumin. In another exemplary aspect, the cryopreserved
membrane composition further comprises physiological saline.
In further exemplary aspects, the disclosed cryopreserved membrane
composition can be provided as part of a kit, which further
comprises instructions for applying the cryopreserved membrane to a
tissue defect. In another exemplary aspect, the kit further
comprises instructions for thawing the cryopreserved composition.
In another exemplary aspect, the kit comprises further instructions
on maintaining the directionality of the membrane while being
applied to the tissue defect. In another exemplary aspect, the
tissue defect is a wound. In another exemplary aspect, the kit
further comprises instructions for removal of the cover. In another
exemplary aspect, the kit further comprises instructions for
maintaining the directionality of the membrane. In another
exemplary aspect, the kit further comprises instructions for
removing the membrane from the base.
All publications and patent applications mentioned in the
specification are indicative of the level of those skilled in the
art to which this invention pertains. All publications and patent
applications are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
Although the foregoing invention has been described in some detail
by way of illustration and example for purposes of clarity of
understanding, certain changes and modifications may be practiced
within the scope of the appended claims.
* * * * *